Stem Cell Tools: Helping Scientists Understand Complex Diseases

Yesterday, we discussed a useful stem cell tool called the CIRM iPSC Repository, which will contain over 3000 human induced pluripotent stem cell (iPSC) lines – from patients and healthy individuals – that contain a wealth of information about human diseases. Now that scientists have access to these lines, they need the proper tools to study them. This is where CIRM’s Genomics Initiative comes into play.

Crunching stem cell data

In 2014, CIRM funded the Genomics Initiative, which created the Center of Excellence in Stem Cell Genomics (CESCG). The goal of the CESCG is to develop novel genomics and bioinformatics tools specifically for stem cell research. These technologies aim to advance our fundamental understanding of human development and disease mechanisms, improve current cell and tissue production methods, and accelerate personalized stem cell-based therapies.

The CESCG is a consortium between Stanford University, the Salk Institute and UC Santa Cruz. Together, the groups oversee or support more than 20 different research projects throughout California focused on generating and analyzing sequencing data from stem or progenitor cells. Sequencing technology today is not only used to decode DNA, but also used to study other genomic data like that provides information about how gene activity is regulated.

Many of the projects within the CESCG are using these sequencing techniques to define the basic genetic properties of specific cell types, and will use this information to create better iPSC-based tissue models. For example, scientists can determine what genes are turned on or off in cells by analyzing raw data from RNA sequencing experiments (RNA is like a photocopy of DNA sequences and is the cell’s way of carrying out the instructions contained in the DNA. This technology sequences and identifies all the RNA that is generated in a tissue or cell at a specific moment).  Single cell RNA sequencing, made possible by techniques such as Drop-seq mentioned in yesterday’s blog, are now further revealing the diversity of cell types within tissues and creating more exact reference RNA sequences to identify a specific cell type.  By comparing RNA sequencing data from single cells of stem cell-based models to previously referenced cell types, researchers can estimate how accurate, or physiologically relevant, those stem cell models are.

Such comparative analyses can only be done using powerful software that can compare millions of sequence data at the same time. Part of a field termed bioinformatics, these activities are a significant portion of the CESCG and several software tools are being created within the Initiative.  Josh Stuart, a faculty member at UC Santa Cruz School of Engineering and a primary investigator in the CESCG, explained their team’s vision:

Josh Stuart

“A major challenge in the field is recognizing cell types or different states of the same cell type from raw data. Another challenge is integrating multiple data sets from different labs and figuring out how to combine measurements from different technologies. At the CESCG, we’re developing bioinformatics models that trace through all this data. Our goal is to create a database of these traces where each dot is a cell and the curves through these dots explain how the cells are related to one another.”

Stuart’s hope is that scientists will input their stem cell data into the CESCG database and receive a scorecard that explains how accurate their cell model is based on a specific genetic profile. The scorecard will help will not only provide details on the identity of their cells, but will also show how they relate to other cell types found in their database.

The Brain of Cells

An image of a 3D brain organoid grown from stem cells in the Kriegstein Lab at UCSF. (Photo by Elizabeth DiLullo)

A good example of how this database will work is a project called the Brain of Cells (BOC). It’s a collection of single cell RNA sequencing data from thousands of fetal-derived brain cells provided by multiple labs. The idea is that researchers will input RNA sequencing data from the stem cell-derived brain cells they make in their labs and the BOC will give them back a scorecard that describes what types of cells they are and their developmental state by comparing them to the referenced brain cells.

One of the labs that is actively involved in this project and is providing the bulk of the BOC datasets is Arnold Kriegstein’s lab at UC San Francisco. Aparna Bhaduri, a postdoctoral fellow in the Kriegstein lab working on the BOC project, outlined the goal of the BOC and how it will benefit researchers:

“The goal of the Brain of Cells project is to find ways to leverage existing datasets to better understand the cells in the developing human brain. This tool will allow researchers to compare cell-based models (such as stem cell-derived 3D organoids) to the actual developing brain, and will create a query-able resource for researchers in the stem cell community.”

Pablo Cordero, a former postdoc in Josh Stuart’s lab who designed a bioinformatics tool used in BOC called SCIMITAR, explained how the BOC project is a useful exercise in combining single cell data from different external researchers into one map that can predict cell type or cell fate.

“There is no ‘industry standard’ at the moment,” said Cordero. “We have to find various ways to perform these analyses. Approximating the entire human cell lineage is the holy grail of regenerative medicine since in theory, we would have maps of gene circuits that guide cell fate decisions.”

Once the reference data from BOC is ready, the group will use a bioinformatics program called Sample Psychic to create the scorecards for outside researchers. Clay Fischer, project manager of the CESCG at UC Santa Cruz, described how Sample Psychic works:

Clay Fischer

“Sample Psychic can look at how often genes are being turned off and on in cells. It uses this information to produce a scorecard, which shows how closely the data from your cells maps up to the curated cell types and can be used to infer the probability of the cell type.”

The BOC group believes that the analyses and data produced in this effort will be of great value to the research community and scientists interested in studying developmental neuroscience or neurodegeneration.

What’s next?

The Brain of Cells project is still in its early stages, but soon scientists will be able to use this nifty tool to help them build better and more accurate models of human brain development and brain-related diseases.

CESCG is also pursuing stem cell data driven projects focused on developing similar databases and scorecards for heart cells and pancreatic cells. These genomics and bioinformatics tools are pushing the envelope to a day when scientists can connect the dots between how different cell states and cell fates are determined by computational analysis and leverage this information to generate better iPSC-based systems for disease modeling in the lab or therapeutics in the clinic.


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How a Soviet space craft proved an inspiration for CIRM’s latest Board member

blumenthal

George Blumenthal’s life changed on October 4, 1957. That’s the day the Soviet Union launched Sputnik, the world’s first artificial earth satellite. The beach ball-sized satellite marked the start of the space race between the US and the USSR. It also marked the start of Blumenthal’s fascination with science and space.

Fast forward almost 60 years and Dr. Blumenthal, now a world-renowned professor of astronomy and astrophysics and the Chancellor of U.C. Santa Cruz, has been named as the newest member of the CIRM governing Board.

California Lt. Governor Gavin Newsom made the appointment calling Dr. Blumenthal a world-class scientist and forward-looking administrator:

“As a Regent of the University of California, I have been impressed by his deep commitment to expanding educational opportunity for all California students and enhancing research opportunities. I am confident the Chancellor’s vision and leadership will be of immense benefit to the CIRM Board.”

In a news release Dr. Blumenthal said he is looking forward to being part of CIRM:

“The California Institute for Regenerative Medicine is doing outstanding work, and I am delighted to join the Board. CIRM support has advanced stem cell research at UC Santa Cruz and across the state. Public support for this work remains strong, and I look forward to playing a role in securing the future of the institute.”

sputnik

Sputnik

But getting back to Sputnik for a moment. In an article in Valley Vision, the newsletter for Joint Venture Silicon Valley, Dr. Blumenthal said the launch of Sputnik helped fuel his interest in science in general and space in particular.

“Sputnik had a profound effect on American science and it certainly played a part in my interest in space and physics all through high school, college and graduate school,” says Blumenthal. “I intended to become a particle physicist, but after a year in grad school I became more interested in space and astronomy, so I changed from studying the smallest things in the universe to the biggest, like galaxies.”

Dr. Blumenthal became the first in his family to graduate from college. He then went on to enjoy a successful career as a professor of astronomy and astrophysics. His research helped deepen our understanding of galaxies and the cosmos, including the role that dark matter plays in the formation of the structure of the universe. He became the chair of the California Association for Research in Astronomy (CARA), which manages the W. M. Keck Observatory near the summit of Mauna Kea in Hawaii. He also co-authored two of the leading astronomy textbooks, 21st Century Astronomy and Understanding our Universe.

Blumenthal joined the faculty of UC Santa Cruz in 1972 and was named chancellor in 2007. Throughout his career he has been a champion of diversity both at UCSC, where he created the Chancellor’s Advisory Council on Diversity, and throughout the U.C. system, where he served as a member of the Regents’ Study Group on Diversity.

Jonathan Thomas, Chair of the CIRM Board, welcomed Dr. Blumenthal, saying:

“We are honored to have someone with Dr. Blumenthal’s experience and expertise join the Board. As Chancellor at UCSC he has demonstrated a clear commitment to advancing world-class research and earned a reputation as a bold and visionary leader. We look forward to seeing those qualities in action to help advance CIRM’s mission.”

At CIRM we are shooting for the stars, aiming as high as we can to help accelerate stem cell treatements to patients with unmet medical needs. It will be nice having Dr. Blumenthal on Board to help guide us.

Stem cells and prostate cancer are more similar than we thought

Prostate cancer is a scary word for men, no matter how macho or healthy they are. These days however, prostate cancer is no longer a death sentence for them. In fact, many men survive this disease if diagnosed early. However, for those unlucky ones who have more advanced stages of prostate cancer (where the tumor has metastasized and spread to other organs), the typical treatments used to fight the tumors don’t work effectively because advanced tumors become resistant to these therapies.

To help those afflicted with late stage prostate cancer, scientists are trying to understand the nature of prostate cancer cells and what makes them so “deadly”. By understanding the biology behind these tumor cells, they hope to develop better therapies to treat the late-stage forms of this disease.

UCLA scientists Bryan Smith and Owen Witte. (Image credit: UCLA Broad Stem Cell Research Center)

UCLA scientists Bryan Smith and Owen Witte. (Image credit: UCLA Broad Stem Cell Research Center)

But don’t worry, help is already on its way. Two groups from the University of California, Los Angeles and the University of California, Santa Cruz published a breakthrough discovery yesterday on the similarity between prostate cancer cells and prostate stem cells. The study was published in the journal PNAS and was led by senior author and director of the UCLA Broad Stem Cell Research Center, Dr. Owen Witte.

Using bioinformatics, Witte and his team compared the gene expression profiles of late-stage, metastatic prostate cancer cells sourced from tumor biopsies of living patients to healthy cell types in the male prostate. Epithelial cells are one of the main cell types in the prostate (they form the prostate glands) and they come in two forms: basal and luminal. When they compared the gene expression profiles of the prostate cancer cells to healthy prostate epithelial cells, they found that the cancer cells had a similar profile to normal prostate epithelial basal stem cells.

Image of a prostate cancer tumor. Green and red represent different stem cell traits and the yellow areas show where two stem cell traits are expressed together. (Image credit: UCLA Broad Stem Cell Research Center)

Image of a prostate cancer tumor. Green and red represent different stem cell traits and the yellow areas show where two stem cell traits are expressed together. (Image credit: UCLA Broad Stem Cell Research Center)

In fact, they discovered a 91-gene signature specific to the basal stem cells in the prostate. This profile included genes important for stem cell signaling and invasiveness. That meant that the metastatic prostate cancer cells also expressed “stem-like” genes.

First author Bryan Smith explained how their results support similar findings for other types of cancers. “Evidence from cancer research suggests that aggressive cancers have stem–cell-like traits. We now know this to be true for the most aggressive form of prostate cancer.”

So what does this study mean for prostate cancer patients? I’ll let Dr. Witte answer this one…

Treatments for early stage prostate cancer are often successful, but therapies that target the more aggressive and late-stage forms of the disease are urgently needed. I believe this research gives us important insight into the cellular nature of aggressive prostate cancer. Pinpointing the cellular traits of cancer — what makes those cells grow and spread — is crucial because then we can possibly target those traits to reverse or stop cancer’s progression. Our findings will inform our work as we strive to find treatments for aggressive prostate cancer.


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