CIRM grantees at Gladstone Institute receive $5 million to expand stem cell program

The Gladstone Institutes in San Francisco are set to expand their stem cell research program with a $5 million gift from the Roddenberry Foundation.

The independent Institute, which is associated with the University of California, San Francisco, has received $24 million in funding from CIRM (you can see a complete list of those awards here). The 14 awards fund training new stem cell scientists, creating a lab facility where Gladstone scientists can share stem cell resources and awards to aid in creating reprogrammed stem cells (known as iPS cells) and treat cardiovascular diseases and HIV/AIDS, among others.

The Roddenberry gift will expand these existing areas of expertise among Gladstone scientists by creating the Roddenberry Center for Stem Cell Biology and Medicine - named after Gene Roddenberry, who created "Star Trek".

A story by Erin Allday at the San Francisco Chronicle quotes Rod Roddenberry, Gene Roddenberry's son:

"We don't fool ourselves into thinking we're going to cure Alzheimer's or heart disease overnight, but if they tell us they are breaking ground and moving forward, we definitely want to help them do it."

"It was amazing to go up to Gladstone and look through a microscope and see a sheet of beating heart cells, and know they came from skin cells," Roddenberry said. "Walking around the institute, we met scientists who were passionate and excited by what they were doing. And as corny as it sounds, a lot of them believed in the 'Star Trek' future, a beautiful future."

Allday also spoke with CIRM President Alan Trouson about the Gladstone Institutes:

"Gladstone is small, but it's incredibly effective, and it's ranked very high by scientists around this country as one of the best institutes."

A press release from the Gladstone Institutes about the gift quotes Deepak Srivastava, who directs both stem cell and cardiovascular research at Gladstone:

“Today's biggest challenge for solving disease is getting the investments required to transform our basic-science discoveries into health solutions that can alleviate human suffering.”

Investments like those from CIRM and now the Roddenberry Foundation should help accelerate the translation of basic discoveries by Gladstone scientists into real therapies. This video discusses work by Gladstone scientist Bruce Conklin, who is developing a stem cell method of screening drugs to treat a form of heart disease:



A.A.

Heart, heal theyself

A group of researchers from University College London made a splash this week with their work prodding heart muscle to repair itself. This is big news, given both the number of people who have heart attacks (more than 1 million per year in the US) and the number of stem cell scientists working to regenerate the damage (23 awards worth $46 million from CIRM).

The big problem has been this: The heart appears to have some stem-like cells, but in adults they don't do much. They certainly aren't able to repair damage after a heart attack. When the heart is developing, however, those cells are the major source of new heart muscle. So, what gives? Why can't those cells perform in adults the way they do during development?

A story by Mitch Leslie in ScienceNOW has this to say about the UCL work:

To recapture the cells' youthful vigor, the researchers injected mice with thymosin β4, a compound already undergoing clinical trials as a heart attack treatment because it helps cardiomyocytes survive and spurs the growth of new blood vessels. The researchers then mimicked a heart attack in the animals by tying off one of the arteries that deliver blood to the heart, injuring part of the muscle.

Unlike control mice that didn't appear to fashion any new cardiomyocytes, animals dosed with thymosin β4 made some of the cells, the team reports online today in Nature. The cells infiltrated the damaged zone left by the simulated heart attack and meshed with other cardiomyocytes physically and electrically, allowing them to beat. They also seemed to prevent some of the damage that can result from a heart attack. Magnetic resonance imaging scans showed that the hearts of mice that had received thymosin β4 had smaller scars and were able to pump more blood with each contraction than were the hearts of untreated rodents.

The news is good, but thymosin β4 wasn't all that efficient. The group is hoping to find other compounds that can more effectively prod progenitors into action.

This work is interesting, too, because it shows the interplay between stem cell science and traditional drug-based medicine. Transplantation therapies are what grab the stem cell headlines. But studying how stem cells normally function can also lead to the development of new drugs, such as ones that could help the heart heal itself.

The ScienceNOW story quotes CIRM grantee Deepak Srivastava, who made headlines last year when he was able to directly transform support cells in the heart into heart muscle — a trick he'd like to replicated not in a lab dish but in an actual heart.

The study "provides strong evidence that there is a population of cells from the epicardium that can turn into new muscle," Srivastava says. "The real question is how robust is the process [of cell transformation] and how can it be improved." He recommends that researchers also investigate whether the cells can rebuild cardiac muscle during heart failure, a condition that afflicts some 5 million U.S residents and causes the organ to progressively weaken.

A.A.

Genes at the heart of heart deformities found through stem cell studies

CIRM grantees at The Gladstone Institutes have, over the past few years, been hard at work learning about the origins of heart deformities by studying how stem cells mature into heart tissue.

What they've learned is that small relatives of DNA, called micro-RNAs, help control when and how cells mature into heart tissue (blogged about here and here) or blood vessels (blogged about here). In recent work out of the lab of Deepak Srivastava, they also discovered three genes are activated by a key micro-RNA whose absence can lead to heart deformities. That work is published in the April 17 Developmental Cell.

The work was in fruit flies, but many basic discoveries in fruit flies directly translate to humans.

Isabelle King, who works with Srivastava at the Gladstone Institutes and led the study, said discovering those genes could help scientists understand and treat cases where the heart failed to form properly in development. A press release from Gladstone quotes King:

“In the fetal heart, subtle changes in gene dosage and timing can yield heart defects in children.”

This work is a great example of how basic stem cell research can lead to new areas to explore for disease therapies. People often think of stem cell therapies as exclusively transplantation therapies in which stem cells and their derivatives are transplanted into a diseased organ to restore function. We do fund scientists trying to do just that, but we also fund basic stem cell scientists who are discovering how diseases arise, and the genes responsible. These discoveries made possible by studying stem cells could lead to new drugs or other interventions that have nothing to do with transplantation.

On the topic of basic research, we'll be funding our third round of Basic Biology Awards at our governing board meeting next week (here are review summaries of those applications). These awards are intended to foster the kinds of basic stem cell and disease discoveries that keep new ideas — and eventual cures — flowing.


Developmental Cell, April 17, 2011
CIRM funding: Deepak Srivastava (RC1-00142); Li Quan (TG2-01160)

Skin cells become beating heart cells in a lab dish

Scripps Research scientists have
created mature heart muscle cells
directly from skin cells.

Eventually, directly reprogramming one type of adult cell into another is going to be old news. For now, the entire field is new enough that each time scientists pluck one adult cell type and coerce it to become another, it’s exciting.

The most recent example comes from CIRM grantees at Scripps Research Institute, who converted mouse skin cells into beating heart cells in just 11 days. A press release quotes senior author Sheng Ding:

“It is like launching a rocket," he said. "Until now, people thought you needed to first land the rocket on the moon and then from there you could go to other planets. But here we show that just after the launch you can redirect the rocket to another planet without having to first go to the moon. This is a totally new paradigm.”

Since 2006, scientists have been able to convert skin cells into embryonic-like iPS cells, which they could then mature into different cell types including heart. Directly converting skin to heart saves time, and could result in more effective therapies. According to the Scripps press release:

When, for example, scientists induce iPS cells to become heart cells, the resulting cells are a mix of heart cells and some lingering iPS cells. Scientists are concerned that giving these new heart cells (along with the remaining pluripotent cells) to patients might be dangerous. When pluripotent cells are injected in mice, they cause cancer-like growths.

Other CIRM grantees who have succeed in direct reprogramming include Marius Wernig at Stanford, who converted skin to nerve, and Deepak Srivastava, who converted heart fibroblasts into heart muscle cells.


Nature Cell Biology, January 30, 2011
CIRM funding: Sheng Ding (RN1-00536-1)

- A.A.

Support Cells Prevent Mature Heart from Repairing Damage

Researchers at the Gladstone Institute of Cardiovascular Disease may have discovered why developing heart muscles cells multiply in numbers while the adult counterparts do not. This finding could lead to therapies that roll back the clocks on heart muscle cells after injury such as a heart attack, allowing those cells to multiply and repair the damage. The researchers specifically looked at the role of cells called fibroblasts, which are packed in the heart amidst the muscle cells. They found that fibroblasts in embryonic mouse hearts release proteins that encourage the muscle cells to divide. In contrast, fibroblasts in adult hearts release proteins that encourage muscle cells to expand in size but actively inhibit the cells from multiplying. That role makes sense in healthy hearts, where new cells aren’t needed, but after injury those fibroblasts prevent the heart from being able to repair itself. The researchers hope this finding could lead to new ways of repairing heart tissue after injury.

Developmental Cell: February 16, 2009
CIRM funding: Deepak Srivastava (RC1-00142), Kathy Ivey (T2-00003)

Related Information: Press Release, Gladstone Institute of Cardiovascular Disease, Srivastava bio

Genetic Factor Enables Immature Cells to Form Normal Heart Tissue

Researchers at the Gladstone Institute for Cardiovascular Disease found a genetic factor that helps in the earliest stages of heart development as the primitive tube loops around on itself and forms the separate chambers. This factor -- a short relative of DNA called microRNA -- has an identical counterpart in humans, leading the researchers to believe that their work in fish is likely to relate directly to human heart development. When the researchers interfered with this microRNA while the heart was developing, the immature heart muscle cells failed to mature and the heart chambers didn’t form normally. These heart muscle precursors are a stage in between the embryonic stem cell and the mature heart muscle cell. The heart is among the first organs to develop and also the most critical. When the heart doesn’t develop properly the embryo dies. What’s more, common birth defects involve abnormalities in how these chambers form. Understanding all the steps between an embryonic stem cell and the mature heart cell could help researchers prevent or treat birth defects of the heart.

Proceedings of the National Academy of Sciences: November 12, 2008
CIRM funding: Kathy Ivey (T2-00003), Deepak Srivastava (RC1-00142)

Related Information: Press release, Gladstone Institute of  Cardiovascular Disease, Srivastava bio

Genetic Factor Influences Heart Muscle Formation from Embryonic Stem Cells

Researchers at the Gladstone Institute for Cardiovascular Disease discovered how two specific tiny genetic factors called microRNAs influence the differentiation of embryonic stem cells into heart muscle. They found that the factors not only drive the versatile cells to become heart, but also actively prevent them from becoming other tissue such as bone adding to their potential to make therapy more specific and targeted for patients.

Cell Stem Cell: March 6, 2008
CIRM funding: Kathey Ivey (T2-00003), E. Hsiao (T2-00003), Deepak Srivastava (RC1-00142)

Related Information: Press release, Gladstone Institute of  Cardiovascular Disease,Srivastava bio