Cancer-causing mutations in blood stem cells may also link to heart disease

Whether we read about it in the news or hear it from our doctor, when we think about the causes of heart disease it’s usually some combination of inheriting bad genes from our parents and making poor life style choices like smoking or eating a diet high in fat and cholesterol. But in a fascinating research published yesterday in the New England Journal of Medicine, scientists show evidence that in some people, heart disease may develop much in the same way that a blood cancer does; that is, through a gradual, lifetime accumulation of mutations in hematopoietic cells, or blood stem cells.

This surprising discovery began as a project, published in 2014, aimed at early detection of blood cancers in the general population. This earlier study focused on the line of evidence that cells don’t become cancerous overnight but rather progress slowly as we age. So, in the case of a blood cancer, or leukemia, a blood stem cell can acquire a mutation that transforms the cell into a pre-cancerous state. When that stem cell multiplies it creates “clones” of the blood stem cell that had the cancer-initiating mutation. It’s only after additional genetic insults that these stem cells become full blown cancers.

The research team, composed of scientists from Brigham and Women’s Hospital as well as the Broad Institute of Harvard and MIT, examined DNA sequences from blood samples of over 17,000 people who didn’t have blood cancer. They analyzed these samples, specifically looking at 160 genes that are often mutated in blood cancer. The results from the 2014 study showed that mutations in these genes in people 40 years and under were few and far between. Interestingly, the frequency noticeably increased in older folks with those 10% over 70 years of age carrying the mutations.

Most of these so-called “clonal hematopoiesis of indeterminate potential”, or CHIP, mutations occurred in three genes called DNMT3A, TET2, and ASXL1. While these mutations were indeed associated with a 10-fold higher risk of blood cancer, the team also saw an unexpected correlation: people with these mutations had a 40% higher overall risk of dying due to other causes compared to those who did not carry the mutations. They pinpointed heart disease as one primary cause of the increased mortality risk.

The current follow-up study not only sought to confirm this correlation between the mutations and heart disease but also show the mutations cause the increased risk. This time around, the team looked for the mutations in a group of four different populations totaling over 8000 people. Again, they saw a correlation between the mutations and the risk of heart disease or a heart attack later in life. One of the team leads, Dr. Sekar Kathiresan from the Broad Institute, talked about his team’s reaction to these results in a Time Magazine interview:

Sekar Kathiresan, Photo: Broad Institute

“We were fully expecting not to find anything here. But the odds of having an early heart attack are four-fold higher among younger people with CHIP mutations.”

 

To show a causal link, they turned to mouse studies. They collected bone marrow stem cells from mice engineered to lack Tet2, one of the three genes that when mutated had been associated with increased risk of heart disease. The bone marrow cells were then transplanted into mice which are prone to have increased blood cholesterol and symptoms of heart disease. The presence of these cells that lacked Tet2 led to increased hardening of major arteries – a precursor to clogged blood vessels, heart disease and heart attacks – compared to mice that received normal bone marrow cells.

Though more work remains, Kathiresan thinks these current results offer some tantalizing therapeutic possibilities:

“This is a totally different type of risk factor than hypertension or hypercholestserolemia [high blood cholesterol] or smoking. And since it’s a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present.”

Stories that caught our eye: An antibody that could make stem cell research safer; scientists prepare for clinical trial for Parkinson’s disease; and the stem cell scientist running for Congress

Antibody to make stem cells safer:

There is an old Chinese proverb that states: ‘What seems like a blessing could be a curse’. In some ways that proverb could apply to stem cells. For example, pluripotent stem cells have the extraordinary ability to turn into many other kinds of cells, giving researchers a tool to repair damaged organs and tissues. But that same ability to turn into other kinds of cells means that a pluripotent stem cell could also turn into a cancerous one, endangering someone’s life.

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Researchers at the A*STAR Bioprocessing Technology Institute: Photo courtesy A*STAR

Now researchers at the Agency for Science, Technology and Research (A*STAR) in Singapore may have found a way to stop that happening.

When you change, or differentiate, stem cells into other kinds of cells there will always be some of the original material that didn’t make the transformation. Those cells could turn into tumors called teratomas. Scientists have long sought for a way to identify pluripotent cells that haven’t differentiated, without harming the ones that have.

The team at A*STAR injected mice with embryonic stem cells to generate antibodies. They then tested the ability of the different antibodies to destroy pluripotent stem cells. They found one, they called A1, that did just that; killing pluripotent cells but leaving other cells unharmed.

Further study showed that A1 worked by attaching itself to specific molecules that are only found on the surface of pluripotent cells.

In an article on Phys.Org Andre Choo, the leader of the team, says this gives them a tool to get rid of the undifferentiated cells that could potentially cause problems:

“That was quite exciting because it now gives us a view of the mechanism that is responsible for the cell-killing effect.”

Reviving hope for Parkinson’s patients:

In the 1980’s and 1990’s scientists transplanted fetal tissue into the brains of people with Parkinson’s disease. They hoped the cells in the tissue would replace the dopamine-producing cells destroyed by Parkinson’s, and stop the progression of the disease.

For some patients the transplants worked well. For some they produced unwanted side effects. But for most they had little discernible effect. The disappointing results pretty much brought the field to a halt for more than a decade.

But now researchers are getting ready to try again, and a news story on NPR explained why they think things could turn out differently this time.

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Viviane Tabar, MD; Photo courtesy Memorial Sloan Kettering Cancer Center

Viviane Tabar, a stem cell researcher at Memorial Sloan Kettering Cancer Center in New York, says in the past the transplanted tissue contained a mixture of cells:

“What you were placing in the patient was just a soup of brain. It did not have only the dopamine neurons, which exist in the tissue, but also several different types of cells.”

This time Tabar and her husband, Lorenz Studer, are using only cells that have been turned into the kind of cell destroyed by the disease. She says that will, hopefully, make all the difference:

“So you are confident that everything you are putting in the patient’s brain will consist of  the right type of cell.”

Tabar and Studer are now ready to apply to the Food and Drug Administration (FDA) for permission to try their approach out in a clinical trial. They hope that could start as early as next year.

Hans runs for Congress:

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Hans Keirstead: Photo courtesy Orange County Register

Hans Keirstead is a name familiar to many in the stem cell field. Now it could become familiar to a lot of people in the political arena too, because Keirstead has announced he’s planning to run for Congress.

Keirstead is considered by some to be a pioneer in stem cell research. A CIRM grant helped him develop a treatment for spinal cord injury.  That work is now in a clinical trial being run by Asterias. We reported on encouraging results from that trial earlier this week.

Over the years the companies he has founded – focused on ovarian, skin and brain cancer – have made him millions of dollars.

Now he says it’s time to turn his sights to a different stage, Congress. Keirstead has announced he is going to challenge 18-term Orange County Republican Dana Rohrabacher.

In an article in the Los Angeles Times, Keirstead says his science and business acumen will prove important assets in his bid for the seat:

“I’ve come to realize more acutely than ever before the deficits in Congress and how my profile can actually benefit Congress. I’d like to do what I’m doing but on a larger stage — and I think Congress provides that, provides a forum for doing the greater good.”

 

 

 

 

 

 

 

 

 

Baseball’s loss is CIRM’s gain as Stanford’s Linda Boxer is appointed to Stem Cell Agency Board

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Dr. Linda Boxer: Photo courtesy Stanford University

One of the things that fascinates me is finding out how people end up in the job they have, the job they love. It is rare that the direction they started out on is the one they end on. Usually, people take several different paths, some intended, some unintended, to get to where they want to be.

A case in point is Dr. Linda Boxer, a renowned and respected researcher and physician at the Stanford School of Medicine, and now the newest member of the CIRM Board (you can read all about that in our news release).

In Dr. Boxer’s case, her original career path was a million miles from working with California’s stem cell agency:

“The first career choice that I recall as a young child was professional baseball—growing up in Minnesota, I was a huge Twins fan—I did learn fairly quickly that this was not likely to be a career that was available for a girl, and it wasn’t clear what one did after that career ended at a relatively young age.”

Fortunately for us she became interested in science.

“I have always been curious about how things work—science classes in grade school were fascinating to me. I was given a chemistry kit as a birthday gift, and I was amazed at what happened when different chemicals were mixed together: color changes, precipitates forming, gas bubbles, explosions (small ones, of course).

Then when we studied biology in middle school, I was fascinated by what one could observe with a microscope and became very interested in trying to understand how living organisms work.

It was an easy decision to plan a career in science.  The tougher decision came in college when I had planned to apply to graduate school and earn a PhD, but I was also interested in human health and disease and thought that perhaps going to medical school made more sense.  Fortunately, one of my faculty advisors told me about combined MD/PhD programs, and that choice seemed perfect for me.”

Along the way she says she got a lot of help and support from her colleagues. Now she wants to do the same for others:

“Mentors are incredibly important at every career stage.  I have been fortunate to have been mentored by some dedicated scientists and physicians.  Interestingly, they have all been men.  There were really very few women available as mentors at the time—of course, that has changed for the better now.  It never occurred to me then that gender made a difference, and I just looked for mentors who had successful careers as scientists and physicians and who could provide advice to someone more junior.

One of the aspects of my role now that I enjoy the most is mentoring junior faculty and trainees.  I don’t think one can have too many mentors—different mentors can help with different aspects of one’s life and career.  I think it is very important for established scientists to give back and to help develop the next generation of physicians and scientists.”

Dr. Boxer is already well known to everyone at CIRM, having served as the “alternate” on the Board for Stanford’s Dr. Lloyd Minor. But her appointment by State Controller Betty Yee makes her the “official” Board member for Stanford. She brings a valuable perspective as both a scientist and a physician.

The Minnesota Twins lost out when she decided to pursue a career in science. We’re glad she did.

 

Stanford scientists devise an algorithm that identifies gene pairs associated with cancer

Using data from human tumor samples, Stanford scientists have developed a new computer algorithm to identify pairs of genes that cause cancer. Their research aims to identify alternative ways to target cancer-causing mutations that have thus far evaded effective clinical treatment.

The study, which was published this week in Nature Communications, was led by senior authors Dr. Ravi Majeti and Dr. David Dill and included two CIRM Bridges interns Damoun Torabi and David Cruz Hernandez.

Identifying Partners in Crime

Cancer cells are notorious for acquiring genetic mutations due to the instability of their genomes and errors in the machinery that repairs DNA. Sometimes these errors create what are called synthetic lethal genes. These are pairs of genes that can cause a cell to die if both genes are defective due to acquired mutations, but a defect in only one of the genes allows a cell to live.

Cancer cells rely on pairs of genes with similar functions for their survival. If one gene is mutated, then the cancer cell depends on the other functional gene, aka its “partner in crime”, to keep it doing its mischief. Scientist are interested in targeting this second partner gene in synthetic lethal pairs in the hopes of developing less toxic cancer therapies that only kill cancer cells instead of healthy ones too.

The Stanford team went on the hunt for synthetic lethal partner genes in data from 12 different human cancers using an algorithm they developed called Mining Synthetic Lethals (MiSL). David Dill explained their strategy in a Stanford Medicine news release:

“We were looking for situations in which, if gene A is mutated, gene Y is amplified to compensate for the loss of function of gene A. Conversely, gene Y is only ever deleted in cells in which gene A is not mutated.”

David Dill. (Credit: L.A. Cicero/Stanford News Service)

They identified a total of 3,120 cancer-causing mutations and over 145,000 potential synthetic lethal partner genes associated with these mutations. Some of these partnerships were identified in other studies, validating MiSL as an effective tool for their purposes, while other partnerships were novel.

Targeting Partners in Crime

One of the new partnerships they discovered was between a mutation in the IDH1 gene, which is associated with acute myeloid leukemia, and a gene called ACACA. The team validated this pair with experiments in the lab proving that defects in both IDH1 and ACACA blocked leukemia cell growth. MiSL identified 89 potential synthetic lethal partners for the leukemia-causing IDH1 mutation, 17 of which they believe could be targeted by existing cancer drugs.

The authors concluded that using computer algorithms to sift through mountains of biological data is a powerful strategy for identifying genetic relationships leveraged by tumors and could advance drug development for different types of cancers.

Ravi Majeti concluded,

“We’re entering a new era of precision health. Using data from real human tumors gives us important, fundamental advantages over using cancer cell lines that often don’t display the same mutation profiles. We’ve found that, although many known cancer-associated mutations are difficult to target clinically, their synthetic lethal partners may be much more druggable.”

Ravi Majeti (Credit: Steve Fisch)

New target for defeating breast cancer stem cells uncovered

Stashed away in most of your tissues and organs lie small populations of adult stem cells. They help keep our bodies functioning properly by replenishing dying or damaged cells. Their ability to make more copies of themselves, as needed, ensures that there’s always an adequate supply set aside. But this very same self-renewing, life-sustaining property of adult stem cells is deadly in the hands of cancer stem cells. Also called tumor-initiating cells, cancer stem cells sustain tumor growth even after chemotherapy and are thought to be a primary cause of cancer relapse.

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Microscopic image of normal mouse mammary ducts. Mammary stem cells are found among basal cells (green). Image courtesy of Toni Celià-Terrassa and Yibin Kang, Princeton University

By studying adult and cancer stem cells side-by-side, Princeton researchers report this week in Nature Cell Biology that they’ve uncovered a common function in both cells types that not only helps explain an adult stem cell’s self-renewing ability but also points to new therapeutic approaches to targeting breast cancer stem cells.

Both adult and cancer stem cells continually resist signals from their environment that encourage them to specialize, or differentiate, into a particular cell type. Once specialized, the cells lose their ability to self-renew and will eventually die off. Now, if all the adult stem cells in an organ followed that instruction, they would eventually become depleted and the organ would lose the ability to repair itself. The same holds true for cancer stem cells which actually would be a good thing since it would lead to the tumor’s death.

The Princeton team first identified a molecule called miR-199a that allows mammary (breast) stem cells to resist differentiation signals by directly blocking the production of a protein called LCOR. Artificially boosting the amount of miR-199a led to a decrease in LCOR levels and an increase in stem cell function. But when LCOR levels were increased, mammary stem cell function was restricted.

The researchers then turned their attention to breast cancer stem cells and found the same miR-199a/LCOR function at work. In a similar fashion, boosting miR-199a levels enhanced cancer stem cell function and increased tumor formation while increasing LCOR restricted the tumor-forming ability of the breast cancer stem cells.

These lab results also matched up with tissue samples taken from breast cancer patients. High miR-199a levels in the samples correlated with low patient survival rates. But those with high levels of LCOR showed a better prognosis.

It turns out that cells in our immune system are responsible for boosting LCOR in mammary and breast cancer stem cells by releasing a protein called interferon alpha. So the presence of interferon alpha nudges mammary stem cells to mature into mammary gland cells and inhibits breast cancer stems from forming tumors. But in the presence of elevated miR-199a levels, mammary and breast cancer stem cells are protected and maintain their numbers by deactivating the interferon alpha/LCOR signal.

If you’re still with me, these results point to miR-199a as a promising target for restoring interferon-alpha’s cancer interfering properties. Team leader Dr. Yibin Kang highlighted this possibility in a Princeton University press release:

“Interferons have been widely used for the treatment of multiple cancer types. These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway.”

Stem cell stories that caught our eye: better ovarian cancer drugs, creating inner ear tissue, small fish big splash

Two drugs are better than one for ovarian cancer (Karen Ring). Earlier this week, scientists from UCLA reported that a combination drug therapy could be an effective treatment for 50% of aggressive ovarian cancers. The study was published in the journal Precision Oncology and was led by Dr. Sanaz Memarzadeh.

Women with high-grade ovarian tumors have an 85% chance of tumor recurrence after treatment with a common chemotherapy drug called carboplatin. The UCLA team found in a previous study that ovarian cancer stem cells are to blame because they are resistant to carboplatin. It’s because these stem cells have an abundance of proteins called cIAPs, which prevent cell death from chemotherapy.

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Ovarian cancer cells (blue) expressing cIAP protein (red) on the left are more sensitive to a combination therapy than cancer cells that don’t express the protein on the right. (UCLA Broad Stem Cell Research Center/Precision Oncology)

Memarzadeh discovered that an experimental drug called birinapant made some ovarian cancer tumors more sensitive to chemotherapy treatment by breaking down cIAPs. This gave her the idea that combining the two drugs, birinapant and carboplatin, might be a more effective strategy for treating aggressive ovarian tumors.

By treating with the two drugs simultaneously, the scientists improved the survival rate of mice with ovarian cancer. They also tested this combo drug treatment on 23 ovarian cancer cell lines derived from women with highly aggressive tumors. The treatment killed off half of the cell lines indicating that some forms of this cancer are resistant to the combination treatment.

When they measured the levels of cIAPs in the human ovarian cancer cell lines, they found that high levels of the proteins were associated with ovarian tumor cells that responded well to the combination treatment. This is exciting because it means that clinicians can analyze tumor biopsies for cIAP levels to determine whether certain ovarian tumors would respond well to combination therapy.

Memarzadeh shared her plans for future research in a UCLA news release,

“I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy.”

In a first, researchers create inner ear tissue. From heart muscle to brain cells to insulin-producing cells, researchers have figured out how to make a long list of different human cell types using induced pluripotent stem cells (iPSCs) – cells taken from the body and reprogrammed into a stem cell-like state.

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Human inner ear organoid with sensory hair cells (cyan) and sensory neurons (yellow). An antibody for the protein CTBP2 reveals cell nuclei as well as synapses between hair cells and neurons (magenta). | Photo: Karl Koehler

This week, a research group at the Indiana University School of Medicine successfully added inner ear cells to that list. This feat, published in Nature Biotechnology, is especially important given the fact that the inner ear is one of the few parts of the body that cannot be biopsied for further examination. With these cells in hands, new insights into the causes of hearing loss and balance disorders may be on the horizon.

The inner ear contains 75,000 sensory hair cells that convert sound waves into electrical signals to the brain. Loud noises, drug toxicity, and genetic mutations can permanently damage the hair cells leading to hearing loss and dizziness. Over 15%  of the U.S. population have some form of hearing loss and that number swells to 67% for people over 75.

Due to the complex shape of the inner ear, the team grew the iPSCs into three dimensional balls of cells rather than growing them as a flat layer of cells on a petri dish. With educated guesses sprinkled in with some trial and error, the scientists, for the time, identified a recipe of proteins that stimulated the iPSCs to transform into inner ear tissue. And like any great recipe, it wasn’t so much the ingredient list but the timing that was key:

“If you apply these signals at the wrong time you can potentially generate a brain instead of an inner ear,” first author Dr. Karl Koehler said in an interview with Gizmodo. “The real breakthrough is that we figured out the exact timing to do each one of these [protein] treatments.”

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Senior author, Eri Hashino, Ph.D., and first author, Karl R. Koehler, Ph.D. Photo: Indiana University

Careful examination shows that the tissue, referred to as organoids, not only contained the sensory hair cells of the inner ear cell but also nerve cells, or neurons, that are responsible for relaying the sound waves to the brain. Koehler explained the importance of this result in a press release:

“We also found neurons, like those that transmit signals from the ear to the brain, forming connections with sensory cells. This is an exciting feature of these organoids because both cell types are critical for proper hearing and balance.”

Though it’s still early days, these iPSC-derived inner ear organoids are a key step toward the ultimate goal of repairing hearing loss. Senior author, Dr. Eri Hashino, talked about the team’s approach to reach that goal:

“Up until now, potential drugs or therapies have been tested on animal cells, which often behave differently from human cells. We hope to discover new drugs capable of helping regenerate the sound-sending hair cells in the inner ear of those who have severe hearing problems.”

This man’s research is no fish tale
And finally, we leave you this week with a cool article and video by STAT. It features Dr. Leonard Zon of Harvard University and his many, many tanks full of zebrafish. This little fish has made a huge splash in understanding human development and disease. But don’t take my word for it, watch the video!

Newest member of CIRM Board is a fan of horses, Star Trek and Harry Potter – oh, and she just happens to be a brilliant cancer researcher too.

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An addition to the family is always a cause for celebration, whether it be a new baby, a puppy, or, in our case, a new Board member. That’s why we are delighted to welcome City of Hope’s Linda Malkas, Ph.D., as the newest member of the CIRM Board.

Dr. Malkas has a number of titles including Professor of Molecular and Cellular Biology at Beckman Research Institute; Deputy Director of Basic Research, Comprehensive Cancer Center, City of Hope; and joint head of the Molecular Oncology Program at the Cancer Center.

Her research focus is cancer and she has a pretty impressive track record in the areas of human cell DNA replication/repair, cancer cell biomarker and therapeutic target discovery. As evidence of that, she discovered a molecule that can inhibit certain activities in cancerous cells and hopes to move that into clinical trials in the near future.

California Treasure John Chiang made the appointment saying Dr. Malkas is “extraordinarily well qualified” for the role. It’s hard to disagree. She has a pretty impressive resume:

  • She served for five years on a National Cancer Institute (NCI) subcommittee reviewing cancer center designations.
  • She has served as chair on several NCI study panels and recently took on an advisory role on drug approval policy with the Food and Drug Administration.
  • She has published more than 75 peer-reviewed articles
  • She sits on the editorial boards of several high profile medical journals.

In a news release Dr. Malkas says she’s honored to be chosen to be on the Board:

“The research and technologies developed through this agency has benefited the health of not only Californians but the nation and world itself. I am excited to see what the future holds for the work of this agency.”

With all this in her work life it’s hard to imagine she has time for a life outside of the lab, and yet she does. She has four horses that she loves to ride – not all at the same time we hope – a family, friends, dogs and cats she likes spending time with. And as if that wasn’t enough to make you want to get to know her, she’s a huge fan of Star Trek, vintage sci-fi movies and Harry Potter.

Now that’s what I call a well-rounded individual. We are delighted to have her join the CIRM Team and look forward to getting her views on who are the greater villains, Klingons or Death Eaters.

 

Don’t Be Afraid: High school stem cell researcher on inspiring girls to pursue STEM careers

As part of our CIRM scholar blog series, we’re featuring the research and career accomplishments of CIRM funded students.

Shannon Larsuel

Shannon Larsuel is a high school senior at Mayfield Senior School in Pasadena California. Last summer, she participated in Stanford’s CIRM SPARK high school internship program and did stem cell research in a lab that studies leukemia, a type of blood cancer. Shannon is passionate about helping people through research and medicine and wants to become a pediatric oncologist. She is also dedicated to inspiring young girls to pursue STEM (Science, Technology, Engineering, and Mathematics) careers through a group called the Stem Sisterhood.

I spoke with Shannon to learn more about her involvement in the Stem Sisterhood and her experience in the CIRM SPARK program. Her interview is below.


Q: What is the Stem Sisterhood and how did you get involved?

SL: The Stem Sisterhood is a blog. But for me, it’s more than a blog. It’s a collective of women and scientists that are working to inspire other young scientists who are girls to get involved in the STEM field. I think it’s a wonderful idea because girls are underrepresented in STEM fields, and I think that this needs to change.

I got involved in the Stem Sisterhood because my friend Bridget Garrity is the founder. This past summer when I was at Stanford, I saw that she was doing research at Caltech. I reconnected with her and we started talking about our summer experiences working in labs. Then she asked me if I wanted to be involved in the Stem Sisterhood and be one of the faces on her website. She took an archival photo of Albert Einstein with a group of other scientists that’s on display at Caltech and recreated it with a bunch of young women who were involved in the STEM field. So I said yes to being in the photo, and I’m also in the midst of writing a blog post about my experience at Stanford in the SPARK program.

Members of The Stem Sisterhood

Q: What does the Stem Sisterhood do?

SL: Members of the team go to elementary schools and girl scout troop events and speak about science and STEM to the young girls. The goal is to inspire them to become interested in science and to teach them about different aspects of science that maybe are not that well known.

The Stem Sisterhood is based in Los Angeles. The founder Bridget wants to expand the group, but so far, she has only done local events because she is a senior in high school. The Stem Sisterhood has an Instagram account in addition to their blog. The blog is really interesting and features interviews with women who are in science and STEM careers.

Q: How has the Stem Sisterhood impacted your life?

SL: It has inspired me to reach out to younger girls more about science. It’s something that I am passionate about, and I’d like to pursue a career in the medical field. This group has given me an outlet to share that passion with others and to hopefully change the face of the STEM world.

Q: How did you find out about the CIRM SPARK program?

SL: I knew I wanted to do a science program over the summer, but I wasn’t sure what type. I didn’t know if I wanted to do research or be in a hospital. I googled science programs for high school seniors, and I saw the one at Stanford University. It looked interesting and Stanford is obviously a great institution. Coming from LA, I was nervous that I wouldn’t be able to get in because the program had said it was mostly directed towards students living in the Bay Area. But I got in and I was thrilled. So that’s basically how I heard about it, because I googled and found it.

Q: What was your SPARK experience like?

SL: My program was incredible. I was a little bit nervous and scared going into it because I was the only high school student in my lab. As a high school junior going into senior year, I was worried about being the youngest, and I knew the least about the material that everyone in the lab was researching. But my fears were quickly put aside when I got to the lab. Everyone was kind and helpful, and they were always willing to answer my questions. Overall it was really amazing to have my first lab experience be at Stanford doing research that’s going to potentially change the world.

Shannon working in the lab at Stanford.

I was in a lab that was using stem cells to characterize a type of leukemia. The lab is hoping to study leukemia in vitro and in vivo and potentially create different treatments and cures from this research. It was so cool knowing that I was doing research that was potentially helping to save lives. I also learned how to work with stem cells which was really exciting. Stem cells are a new advancement in the science world, so being able to work with them was incredible to me. So many students will never have that opportunity, and being only 17 at the time, it was amazing that I was working with actual stem cells.

I also liked that the Stanford SPARK program allowed me to see other aspects of the medical world. We did outreach programs in the Stanford community and helped out at the blood drive where we recruited people for the bone marrow registry. I never really knew anything about the registry, but after learning about it, it really interested me. I actually signed up for it when I turned 18. We also met with patients and their families and heard their stories about how stem cell transplants changed their lives. That was so inspiring to me.

Going into the program, I was pretty sure I wanted to be a pediatric oncologist, but after the program, I knew for sure that’s what I wanted to do. I never thought about the research side of pediatric oncology, I only thought about the treatment of patients. So the SPARK program showed me what laboratory research is like, and now that’s something I want to incorporate into my career as a pediatric oncologist.

I learned so much in such a short time period. Through SPARK, I was also able to connect with so many incredible, inspired young people. The students in my program and I still have a group chat, and we text each other about college and what’s new with our lives. It’s nice knowing that there are so many great people out there who share my interests and who are going to change the world.

Stanford SPARK students.

Q: What was your favorite part of the SPARK program?

SL: Being in the lab every day was really incredible to me. It was my first research experience and I was in charge of a semi-independent project where I would do bacterial transformations on my own and run the gels. It was cool that I could do these experiments on my own. I also really loved the end of the summer poster session where all the students from the different SPARK programs came together to present their research. Being in the Stanford program, I only knew the Stanford students, but there were so many other awesome projects that the other SPARK students were doing. I really enjoyed being able to connect with those students as well and learn about their projects.

Q: Why do you want to pursue pediatric oncology?

SL: I’ve always been interested in the medical field but I’ve had a couple of experiences that really inspired me to become a doctor. My friend has a charity that raises money for Children’s Hospital Los Angeles. Every year, we deliver toys to the hospital. The first year I participated, we went to the hospital’s oncology unit and something about it stuck with me. There was one little boy who was getting his chemotherapy treatment. He was probably two years old and he really inspired to create more effective treatments for him and other children.

I also participated in the STEAM Inquiry program at my high school, where I spent two years reading tons of peer reviewed research on immunotherapy for pediatric cancer. Immunotherapy is something that really interests me. It makes sense that since cancer is usually caused by your body’s own mutations, we should be able to use the body’s immune system that normally regulates this to try and cure cancer. This program really inspired me to go into this field to learn more about how we can really tailor the immune system to fight cancer.

Q: What advice do you have for young girls interested in STEM.

SL: My advice is don’t be afraid. I think that sometimes girls are expected to be interested in less intellectual careers. This perception can strike fear into girls and make them think “I won’t be good enough. I’m not smart enough for this.” This kind of thinking is not good at all. So I would say don’t be afraid and be willing to put yourself out there. I know for me, sometimes it’s scary to try something and know you could fail. But that’s the best way to learn. Girls need to know that they are capable of doing anything and if they just try, they will be surprised with what they can do.

Stem Cell Stories That Caught Our Eye: Three new ways to target cancer stem cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Targeting cancer stem cells. This week, three studies came out with novel ways for targeting cancer stem cells in different types of cancers. Here’s a brief run-down of this trifecta of cancer stem cell-crushing stories:

Take your vitamins! Scientists in the UK were experimenting on cancer stem cells and comparing natural substances to on-the-market cancer drugs to determine whether any of the natural substances were effective at disrupting the metabolism (the chemical reactions that keep cells alive and functioning) of cancer stem cells. Interestingly, they found that ascorbic acid, which you’ll know as Vitamin C, was ten times better at curbing cancer stem cell growth compared to a cancer drug called 2-DG.

Vitamin C has popped up as an anti-cancer treatment in the past when Nobel Laureate Linus Pauling found that it dramatically reduced the death rate in breast cancer patients. However this current study is the first to show that Vitamin C has a direct effect on cancer stem cells.

In coverage by ScienceDaily, the UK team hinted at plans to test Vitamin C in clinical trials:

“Vitamin C is cheap, natural, non-toxic and readily available so to have it as a potential weapon in the fight against cancer would be a significant step. Our results indicate it is a promising agent for clinical trials, and a as an add-on to more conventional therapies, to prevent tumour recurrence, further disease progression and metastasis.”

 

A gene called ZEB1 determines how aggressive brain tumors are. A team from Cedars-Sinai Medical Center was interested to know how cancer stem cells in aggressive brain tumors called gliomas survive, reproduce and affect patient survival. In a study published in Scientific Reports, they studied the genetic information of over 4000 brain tumor samples and found ZEB1, a gene that regulates tumor growth and is associated with patient survival.

They found that patients with a healthy copy of the ZEB1 gene had a higher survival rate and less aggressive tumors compared to patients that didn’t have ZEB1 or had a mutated version of the gene.

In coverage by ScienceDaily, the senior author on the study explained how their study’s findings will allow for more personalized treatments for patients with glioma based on whether they have ZEB1 or not:

“Patients without the gene in their tumors have more aggressive cancers that act like stem cells by developing into an uncontrollable number of cell types. This new information could help us to measure the mutation in these patients so that we are able to provide a more accurate prognosis and treatment plan.”

 

Beating resistant tumors by squashing cancer stem cells. Our final cancer stem cell story today comes from the UCLA School of Dentistry. This team is studying another type of aggressive cancer called a squamous cell carcinoma that causes tumors in the head and neck. Often these tumors resist treatment and spread to a patient’s lymph nodes, which quickly reduces their survival rate.

The UCLA team thought that maybe pesky cancer stem cells were to blame for the aggressive and resistant nature of these head and neck tumors. In a study published in Cell Stem Cell, they developed a mouse model of head and neck carcinoma and isolated cancer stem cells from the tumors of these mice. When they studied these stem cells, they found that they expressed unique proteins compared to non-cancer cells. These included Bmi1, a well-known stem cell protein, and AP-1, a transcription factor protein that regulates other cancer genes.

At left, head and neck squamous cell carcinoma invasive growth, and at right, cancer stem cells (shown in red) in head and neck squamous cell carcinoma. (Image Demeng Chen and Cun-Yu Wang/UCLA)

After identifying the culprits, the team developed a new combination strategy that targeted the cancer stem cells while also killing off the tumors using chemotherapy drugs.

In a UCLA Newsroom press release, the lead scientist on the study Dr. Cun-Yu Wang explained the importance of their study for the future treatment of cancer and solid tumors:

“This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.”

Stem cell stories that caught our eye: drug safety for heart cells, worms hijack plant stem cells & battling esophageal cancer

Devising a drug safety measuring stick in stem cell-derived heart muscle cells
One of the mantras in the drug development business is “fail early”. That’s because most of the costs of getting a therapy to market occur at the later stages when an experimental treatment is tested in clinical trials in people. So, it’s best for a company’s bottom line and, more importantly, for patient safety to figure out sooner rather than later if a therapy has dangerous toxic side effects.

Researchers at Stanford reported this week in Science Translational Medicine on a method they devised that could help weed out cancer drugs with toxic effects on the heart before the treatment is tested in people.

In the lab, the team grew beating heart muscle cells, or cardiomyocytes, from induced pluripotent stem cells derived from both healthy volunteers and kidney cancer patients. A set of cancer drugs called tyrosine kinase inhibitors which are known to have a range of serious side effects on the heart, were added to the cells. The effect of the drugs on the heart cell function were measured with several different tests which the scientists combined into a single “safety index”.

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A single human induced pluripotent stem cell-derived cardiomyocyte. Cells such as these were used to assess tyrosine kinase inhibitors for cardiotoxicity in a high-throughput fashion. Credit: Dr. Arun Sharma at Dr. Joseph Wu’s laboratory at Stanford University

They found that the drugs previously shown to have toxic effects on patients’ hearts had the worst safety index values in the current study. And because these cells were in a lab dish and not in a person’s heart, the team was able to carefully examine cell activity and discovered that the toxic effects of three drugs could be alleviated by also adding insulin to the cells.

As lead author Joseph Wu, director of the Stanford Cardiovascular Institute, mentions in a press release, the development of this drug safety index could provide a powerful means to streamline the drug development process and make the drugs safer:

“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients. It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects”

Worm feeds off of plants by taking control of their stem cells
In what sounds like a bizarre mashup of a vampire movie with a gardening show, a study reported this week pinpoints how worms infiltrate plants by commandeering the plants’ own stem cells. Cyst nematodes are microscopic roundworms that invade and kill soybean plants by sucking out their nutrients. This problem isn’t a trivial matter since nematodes wreak billions of dollars of damage to the world’s soybean crops each year. So, it’s not surprising that researchers want to understand how exactly these critters attack the plants.

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A nematode, the oblong object on the left, activates the vascular stem cell pathway in the developing nematode feeding site on a plant root. Credit: Xiaoli Guo, University of Missouri

Previous studies by Melissa Goellner Mitchum, a professor at the University of Missouri, had shown that the nematodes release protein fragments, called peptides, near a plant’s roots that help divert the flow of plant nutrients to the worm.

“These parasites damage root systems by creating a unique feeding cell within the roots of their hosts and leeching nutrients out of the soybean plant. This can lead to stunting, wilting and yield loss for the plant,” Mitchum explained in a press release.

In the current PLOS Pathogens study, Mitchum’s team identified another peptide produced by the nematode that is identical to a plant peptide that instructs stem cells to form the plant equivalent of blood vessels. This devious mimicking of the plant peptides is what allows the nematode to trick the plant stem cells into building vessels that reroute the plants’ nutrients directly to the worm.

Mitchum described the big picture implications of this fascinating discovery:

“Understanding how plant-parasitic nematodes modulate host plants to their own benefit is a crucial step in helping to create pest-resistant plants. If we can block those peptides and the pathways nematodes use to overtake the soybean plant, then we can enhance resistance for this very valuable global food source.”

Finding vulnerabilities in treatment-resistant esophageal cancer stem cells

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Illustration of radiation therapy for esophageal cancer.
Credit: Cancer Research UK

The incidence of esophageal cancer has increased more than any other disease over the past 30 years. And while some patients respond well to chemotherapy and radiation treatment, most do not because the cancer becomes resistant to these treatments.

Focusing on cancer stem cells, researchers at Trinity College Dublin have identified an approach that may overcome treatment resistance.

Within tumors are thought to lie cancer stem cells that, just like stem cells, have the ability to multiply indefinitely. Even though they make up a small portion of a tumor, in some patients the cancer stem cells evade the initial rounds of treatment and are responsible for the return of the cancer which is often more aggressive. Currently, there’s no effective way to figure out how well a patient with esophageal cancer will response to treatment.

In the current study published in Oncotarget, the researchers found that a genetic molecule called miR-17 was much less abundant in the esophageal cancer stem cells. In fact, the cancer stem cells with the lowest levels of miR-17, were the most resistant to radiation therapy. The researchers went on to show that adding back miR-17 to the highly resistant cells made them sensitive again to the radiation. Niamh Lynam-Lennon, the study’s first author, explained in a press release that these results could have direct clinical applications:

“Going forward, we could use synthetic miR-17 as an addition to radiotherapy to enhance its effectiveness in patients. This is a real possibility as a number of other synthetic miR-molecules are currently in clinical trials for treating other diseases.”