Spotlight on CIRM Grantee Joe Wu: Clinical Trials for Heart Disease in a Dish?

It’s always exciting to read a science article featuring a talented scientist who is breaking boundaries in the field of regenerative medicine. It’s especially exciting to us at CIRM when the scientist is a CIRM grantee.

Last week, OZY published a fun and inspiring piece on Stanford scientist Joe Wu. Dr. Wu is the Director of the Stanford Cardiovascular Institute and his lab studies how stem cells (both adult and pluripotent) function and how they can be used to model heart diseases and screen for new drug therapies. He also is a CIRM grantee and has a Disease Team Therapy Development grant that aims to clinically test human embryonic stem cell-derived cardiomyocytes (heart cells) in end stage heart failure patients.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

The OZY piece does a great job of highlighting Dr. Wu’s recent efforts to use human induced pluripotent stem cells (iPS cells) to make heart tissue in a dish and model cardiovascular disease. And without getting too technical, the article explains Dr. Wu’s larger mission to combine precision medicine and stem cell research to identify drugs that would be best suited for specific patient populations.

The article commented,

“He envisions treatments based on an individual’s own iPS cells. For example, a popular breast cancer drug has an 8 percent chance of giving patients heart failure. In Wu’s world, we’d test the drug on stem cells first, and if a patient lands in that 8 percent, begin treatment for the side effects preemptively or avoiding the drug totally and avoiding heart failure, too.”

Basically, Dr. Wu sees the future of clinical trials in a dish using human stem cells. “His goal is to take these stem cells from thousands of patients to create a genetically diverse enough bank that will allow for “clinical trials in a dish” — Wu’s go-to phrase.”

Instead of following the traditional drug development paradigm that takes more than 10 years, billions of dollars, and unfortunately usually ends in failure, Dr. Wu wants to follow an accelerated path where stem cells are used for drug toxicity and efficacy testing.

This alternative path could improve overall drug development and approval by the FDA. The article explained,

“Testing drugs on stem cells will give big pharma and the FDA vastly improved heads up for toxic complications. Stem cells are “absolutely” the best avenue going forward, says Norman Stockbridge, director of the division of cardiovascular and renal products at the FDA’s Center for Drug Evaluation and Research.”

Not everyone is on the same page with Dr. Wu’s bold vision of the future of precision medicine, stem cells, and treatments for heart disease. Some believe he is overly ambitious, however top scientists in the stem cell field have praised Dr. Wu’s “systematic approach” to research and how he doesn’t stop at data discovery, he focuses on the big picture and how his work can ultimately help patients.

You can read more about Dr. Wu’s research on his lab website and I highly encourage you to check out the OZY article which is a great example of science communication for the general public.


Related Links:

Multi-Talented Stem Cells: The Many Ways to Use Them in the Clinic

CIRM kicked off the 2016 International Society for Stem Cell Research (ISSCR) Conference in San Francisco with a public stem cell event yesterday that brought scientists, patients, patient advocates and members of the general public together to discuss the many ways stem cells are being used in the clinic to develop treatments for patients with unmet medical needs.

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, an Investigator at the Gladstone Institutes and UCSF Professor, moderated the panel of four scientists and three patient advocates. He immediately captured the audience’s attention by showing a stunning video of human heart cells, beating in synchrony in a petri dish. Conklin explained that scientists now have the skills and technology to generate human stem cell models of cardiomyopathy (heart disease) and many other diseases in a dish.

Conklin went on to highlight four main ways that stem cells are contributing to human therapy. First is using stem cells to model diseases whose causes are still largely unknown (like with Parkinson’s disease). Second, genome editing of stem cells is a new technology that has the potential to offer cures to patients with genetic disorders like sickle cell anemia. Third, stem cells are known to secrete healing factors, and transplanting them into humans could be beneficial. Lastly, stem cells can be engineered to attack cancer cells and overcome cancer’s normal way of evading the immune system.

Before introducing the other panelists, Conklin made the final point that stem cell models are powerful because scientists can use them to screen and develop new drugs for diseases that have no treatments or cures. His lab is already working on identifying new drugs for heart disease using human induced pluripotent stem cells derived from patients with cardiomyopathy.

Scientists and Patient Advocates Speak Out

Malin Parmar, Lund University

Malin Parmar, Lund University

The first scientist to speak was Malin Parmar, a Professor at Lund University. She discussed the history of stem cell development for clinical trials in Parkinson’s disease (PD). Her team is launching the first in-human trial for Parkinson’s using cells derived from human pluripotent stem cells in 2016. After Parmar’s talk, John Lipp, a PD patient advocate. He explained that while he might look normal standing in front of the crowd, his PD symptoms vary wildly throughout the day and make it hard for him to live a normal life. He believes in the work that scientists like Parmar are doing and confidently said, “In my lifetime, we will find a stem cell cure for Parkinson’s disease.”

Adrienne Shapiro, Patient Advocate

Adrienne Shapiro, Patient Advocate

The next scientist to speak was UCLA Professor Donald Kohn. He discussed his lab’s latest efforts to develop stem cell treatments for different blood disorder diseases. His team is using gene therapy to modify blood stem cells in bone marrow to treat and cure babies with SCID, also known as “bubble-boy disease”. Kohn also mentioned their work in sickle cell disease (SCD) and in chronic granulomatous disease, both of which are now in CIRM-funded clinical trials. He was followed by Adrienne Shapiro, a patient advocate and mother of a child with SCD. Adrienne gave a passionate and moving speech about her family history of SCD and her battle to help find a cure for her daughter. She said “nobody plans to be a patient advocate. It is a calling born of necessity and pain. I just wanted my daughter to outlive me.”

Henry Klassen (UC Irvine)

Henry Klassen, UC Irvine

Henry Klassen, a professor at UC Irvine, next spoke about blinding eye diseases, specifically retinitis pigmentosa (RP). This disease damages the photo receptors in the back of the eye and eventually causes blindness. There is no cure for RP, but Klassen and his team are testing the safety of transplanting human retinal progenitor cells in to the eyes of RP patients in a CIRM-funded Phase 1/2 clinical trial.

Kristen MacDonald, RP patient

Kristen MacDonald, RP patient

RP patient, Kristen MacDonald, was the trial’s first patient to be treated. She bravely spoke about her experience with losing her vision. She didn’t realize she was going blind until she had a series of accidents that left her with two broken arms. She had to reinvent herself both physically and emotionally, but now has hope that she might see again after participating in this clinical trial. She said that after the transplant she can now finally see light in her bad eye and her hope is that in her lifetime she can say, “One day, people used to go blind.”

Lastly, Catriona Jamieson, a professor and Alpha Stem Cell Clinic director at UCSD, discussed how she is trying to develop new treatments for blood cancers by eradicating cancer stem cells. Her team is conducting a Phase 1 CIRM-funded clinical trial that’s testing the safety of an antibody drug called Cirmtuzumab in patients with chronic lymphocytic leukemia (CLL).

Scientists and Patients need to work together

Don Kohn, Catriona Jamieson, Malin Parmar

Don Kohn, Catriona Jamieson, Malin Parmar

At the end of the night, the scientists and patient advocates took the stage to answer questions from the audience. A patient advocate in the audience asked, “How can we help scientists develop treatments for patients more quickly?”

The scientists responded that stem cell research needs more funding and that agencies like CIRM are making this possible. However, we need to keep the momentum going and to do that both the physicians, scientists and patient advocates need to work together to advocate for more support. The patient advocates in the panel couldn’t have agreed more and voiced their enthusiasm for working together with scientists and clinicians to make their hopes for cures a reality.

The CIRM public event was a huge success and brought in more than 150 people, many of whom stayed after the event to ask the panelists more questions. It was a great kick off for the ISSCR conference, which starts today. For coverage, you can follow the Stem Cellar Blog for updates on interesting stem cell stories that catch our eye.

CIRM Public Stem Cell Event

CIRM Public Stem Cell Event

Women in Bio on The Influential Paths of Great Visionary Leaders

Powerful women made powerful statements last week at the Women in Bio (WIB) Plenary Event during the 2016 BIO International Convention. A panel of influential women leaders discussed difficult yet critical topics, such as how to brand yourself as a woman in a male-dominated industry, the importance of side hustles, and how to close the gender gap. It was a dynamic and inspiring event that engaged both men and women in the audience in productive conversation about how we can all work together to support women in the life sciences industry.

The panel was moderated by Nicole Fisher, the Founder and CEO of HHR Strategies and Forbes Contributer, and the speakers included Renee Compton Ryan, VP of Venture Investments at Johnson & Johnson and Frances Colón, Deputy Science and Technology Adviser to Secretary of State John Kerry.

Frances Colon, Renee Ryan, Nicole Fisher.

Frances Colon, Renee Ryan, Nicole Fisher.

The panel was more of a fire-side chat with the three woman talking intimately at a small coffee table, first sharing stories about their career paths and the road blocks along the way, and then delving into the controversial topics that women in the life sciences face.

Career Paths of Influential Women

Nicole told her story about how she got into the healthcare space. She started by ghostwriting about healthcare, innovation, and politics for the Congressional Budget Office director. Her passion turned into an opportunity with Forbes where she now runs the Health Innovation and Policy page and eventually into her company HHR Strategies which focuses on healthcare and human rights.

Renee discussed how she started as an investment banker in healthcare and made an investment in a company that benefitted patients. This experience made her want to be a part of the solution for patients, which she described as “a calling we are all fortunate to have,” and ultimately brought her to her current position at J&J.

After completing a Ph.D. in developmental neurobiology, Frances switched gears and found her strengths and assets in science policy and communications. She wanted to bring science into international affairs and shared that her mission now is to “make science cool to political scientists and diplomats to the point where my job becomes irrelevant.”

Other Panel Highlights

Branding

Renee’s advice on branding was, “challenge yourself to know your brand, and revisit your brand”. Everyone builds a resume chronologically, but she forces herself to revisit her resume every two years. Her trick is to flip the resume over to the blank side and list all her skills but do it through a different lens so you can have perspective. This process helps her decide where she wants to grow and learn.

Having Side Hustles

Frances mentioned the importance of having “side hustles”. These are things that you are really passionate about that will also build on your strengths, raise your visibility and help you take your brand to the next level. She mentioned two side hustles in particular, a non-profit she founded that supports the Puerto Rican Diaspora Network and a group she organized called the Science Technology Table, which brings together government and the private sector to discuss trending topics in science, tech and innovation. Nicole chimed in and said that all three of her side hustles have turned into companies or big opportunities that have significantly advanced her career.

Closing the Gender Gap, No More Manels!

The panelists had much to say about closing the gender gap. Renee encouraged women in high-up positions to mentor other women that show promise and to be a hands-on mentor. She also said that everyone in the biotech and pharma industries should be studying the data to see why there are less women in the life sciences and what can be done about it.

Frances said that the gender policies at companies need to change, and that people at companies have to hold each other accountable and have the conversations that can create change. One of her key points that got a laugh from the crowd was getting rid of “manels”, or all men panels, which are prevalent at major conferences in the biotech and healthcare space. She also spoke about how we need to strive for 50/50 representation on boards and executive management.

What the audience had to say

The panel was a hit with the Women in Bio audience. Dr. Leah Makley, a WIB member and Founder and CSO of ViewPoint Therapeutics, had this to say about the event,

Leah Makley

Leah Makley

“The panelists shared candid wisdom from their own career trajectories, passions, and ‘side hustles’ that far surpassed the typical depth of career panels.  Moreover, I thought Nicole Fisher did an exceptional job of framing the conversation and asking provocative questions.”

She also spoke about the importance of the WIB community and the resources they offer:

“WIB is a supportive community of powerful, inspiring women. Both the members and the events tend to be action- and solution-oriented, and I’ve walked away from each event I’ve attended with new insights, perspectives, and energy. I’m so grateful that this resource exists.”

Marco Chacon

Marco Chacon

A moment that really stood out in my mind was a moving speech by Marco Chacon, Founder of Paragon Bioservices, and a WIB sponsor. Marco shared that he recently attended a meeting in Boston and listened in on a few diversity forums. He was appalled to hear the statistics on gender diversity in the executive suite and boards of directors in biotech and pharma. Passionately he said, “This has got to change, and to the degree that I can affect this in some way, I can assure you I will do so.”

Final Thoughts

Influential leaders like Nicole, Renee, Frances, and Marco and organizations like Women in Bio, are laying the groundwork for the career advancement of women in science. This event was a great reminder that the issues facing women in the life sciences industry can be addressed in the immediate future if we continue the conversation and challenge one another to create change.

Filling the Holes in our Understanding of Stem Cell Fate

How does a single-celled human embryo transform into a human body with intricate organ systems containing trillions of specialized cells? Step into any college lecture discussing this question and I bet “transcription factors” is a phrase you’ll often hear.

Transcription factors are DNA-binding proteins that act as cell fate control switches during development. For cells destined to become, say muscle tissue, transcription factors bind DNA and help activate muscle-specific genes or keep non-muscle-specific genes silent. And so it goes for all other cell types as they form inside the growing embryo.

But file this blog entry under “Hold up a moment” because in research published today in Stem Cell Reports, CIRM-funded scientists at U.C. San Diego (UCSD) pinpoint another cellular process that appears equally as important as transcription factors in cell fate decisions. The process they studied is called nonsense-mediated mRNA decay (NMD). To go into details about NMD we need to first delve a bit more into transcription factors.

A bit of molecular biology 101
When a gene is said to be activated, or “turned on”, that’s just shorthand for describing the process of transcription in which a stretch of DNA corresponding to a gene is “read” by cell machinery and transcribed into messenger RNA (mRNA). The mRNA is then translated into a string of amino acids which forms a particular protein. By binding to the DNA in the vicinity of a gene, the transcription factors provide a physical platform for the transcribing machinery to form the mRNA. Frequent transcribing leads to more mRNA and more protein.

transcription_2

Transcription and translation: turning genes on to produce proteins (image: tokresource.org)

400px-Vertebratemechanism

The nonsense mRNA decay (NMD) pathway (Wikipedia)

The NMD pathway regulates transcription from the opposite end of the process by promoting the degradation of mRNAs. It was once thought to only be involved in getting rid of mRNAs that contain transcribing errors but more recent studies have shown that NMD has roles in normal cell functions. For instance, the UCSD team had shown that neural stem cells contain high levels of NMD which must be reduced to allow those stem cells to specialize into neurons. In the current paper, the team sought to better understand these underlying mechanisms that enable the NMD pathway to regulate development.

To accomplish this goal, NMD function was examined during the very early stages of human development using human embryonic stem cells (hESC). All adult tissues are derived from the three germ layers that form during embryogenesis: endoderm (which gives rise to lung and gut), mesoderm (which gives rise to muscle, bone, blood) and ectoderm (which gives rise to skin and neurons). When the researchers grew the hESCs under conditions that favored endoderm formation, they observed dramatically reduced levels of NMD activity. But growing hESC toward mesoderm and ectoderm fates, led to increased levels of NMD. So these very early forks in the road of cell fate decisions led to diverging levels of NMD.

NMD activities: cell fate bystander or participant?
But does this change in NMD activity play a direct role during the specialization of hESCs? To answer this question, the team focused on the manipulating NMD activity as hESCs formed into endoderm. Instead of the natural decrease in NMD proteins during endodermal formation, NMD levels were artificially maintained at high levels. Sure enough, this hampered the ability of the hESCs to take on properties of endodermal cells and instead they kept hallmarks of stem cells. Approaching this analysis from the opposite angle, NMD factors were removed from the hESCs under conditions that should block endoderm formation. In support of the previous experiment, this artificial drop in NMD activity led to the initiation of endodermal differentiation.

Further experiments determined that NMD activity specifically inhibits TGF-b, a protein that signals cells toward an endoderm fate. Conversely, the team’s results also suggest that NMD stimulates BMP which is an important signal for a mesoderm fate. So just like transcription factors, the activity of NMD modulates the balance of other proteins which ultimately direct the fate of a cell’s identity. In fact, the TGF- b and BMP pathways themselves stimulate the actions of transcription factors so there’s likely some cooperation going with these factors and NMD. We reached out to UCSD professor Miles Wilkinson, the principal investigator for this study, to get his team’s reaction to their results:

“Most of what we know about human embryonic stem cell fate revolves around the role of factors that regulate RNA synthesis – transcription factors.  In our study, we examined the other side of the coin – the role of factors required for a selective RNA decay pathway.  We were surprised to find that not only did the NMD RNA decay pathway influence embryonic cell differentiation, but it is critical for cell fate decisions through its effect on signaling pathways.  Thus, we envisage that RNA decay pathways and transcriptional pathways converge on signaling pathways to control embryonic stem cell fate.”

 

And a better understanding of how embryonic stem cell fate is controlled could help optimize stem cell-based therapies for a given tissue or organ. Whatever the case, it shouldn’t be long before future college students in a developmental biology class will hear “NMD” in the same breath as “transcription factors”.

BIO 2016: IMAGINE Curing Disease and Saving Lives Part 2

As promised, here is Part 2 of our blog coverage on the BIO International Convention currently ongoing in San Francisco. Here are a few more insights on the talks we attended and highlights of other coverage from top biotech journalists and media outlets.

Keynote with Dr. Bennet Omalu and Will Smith on “Concussion”

If you haven’t seen the movie Concussion, add it to your watch list right now. It’s certainly at the top of mine after listening to Nigerian-American doctor Bennet Omalu share his story about how he single-handedly changed the way the National Football League (NFL) and the world views concussions and brain science.

Will Smith and Dr. Bennet Omalu at #BIO2016

Will Smith and Dr. Bennet Omalu at #BIO2016

In this keynote address, Dr. Omalu sat down with actor Will Smith, who portrays Dr. Omalu in the movie, to discuss how knowledge and truth precipitates evolution. Because of his passion for seeking the truth, Omalu’s autopsy of former NFL player Mike Webster led to the first diagnosis of chronic traumatic encephalopathy (CTE). Omalu’s main message was that faith and science go hand in hand. “Faith searches for truth and science searches for truth. There is no end to truth.” He also emphasized that while the truth can be inconvenient, it’s worth pursuing because truth is empowering.

For Will Smith, portraying Dr. Omalu in Concussion, was both an honor and a duty. As a parent of a son who plays football, he was compelled to tell this story and share this knowledge with parents around the world. Smith was so motivated to take on Omalu’s character that he even watched Omalu conduct four autopsies so he could really understand both the man and the science behind CTE.

This dynamic conversation was the highlight of BIO, and you can read more details about it in this article by Eleena Korban of BIOtechNOW. 

Fireside chat with US FDA Commissioner Robert Califf

Robert Califf and Steve Usdin

Robert Califf and Steve Usdin

Robert Califf, the Commissioner of the US Food and Drug Administration, sat down with Steve Usdin, the Senior Editor with BioCentury, to discuss the most important topics facing the FDA right now. Here are some of his main points:

  • FDA will focus more on patient engagement. Califf said that patients should be involved from the beginning and not just be the recipients of the end product. He also touched on risk tolerance for patients and that it can vary based on disease. The FDA wants to engage patients, advocacy groups, and industry on this topic so that patients can make more educated decisions about their treatment options.
  • The cost of clinical trials is going up 3-4 times the consumer price index which is not sustainable. Califf suggested that we can use integrated health systems and already available data from electronic medical records and patient registries to reduce the costs of large clinical trials. He commented, “The question is, can you create a different playing field that would radically reduce the cost of clinical trials while actually getting us better data about what people really care about and solve their problems related to the use of our products. I think we are close to that point now.”
  • Califf mentioned the FDA’s role in President Obama’s Precision Medicine Initiative as a step towards radically accelerating the rate of drug development. The FDA is partnering with the NIH to create a cloud-based workspace where genetic information on disease can be stored, shared, and studied.
  • Lastly, Califf mentioned how the FDA is creating a virtual center of excellence for cancer research as part of the Cancer Moonshot Initiative. He said that the FDA needs to do a better job of collaborating across its different product centers and that drug devices and biologics will be brought together starting first in the oncology space, and then eventually rolled out to other disease areas. On the clinical side, they will focus on patient involvement and the needs of cancer patients.

More coverage on the FDA fireside chat from BIOtechNOW

 Final Thoughts

While BIO ends today, the partnerships, conversations, and innovation certainly will not. In just four short days, the vibrant and eager atmosphere of BIO has transformed this year’s theme of Imagination into one of hopeful reality. Curing disease and saving lives might not be in the immediate future, but after what I’ve seen at BIO, I’m confident that the groundwork has been laid out to accelerate us down this path.


Other #BIO2016 coverage

IMAGINE Curing Disease and Saving Lives: BIO 2016 Part 1

Did you hear that? It’s the sound of more than 15,000 people taking a collective breath. That’s because we are now at the halfway point of the 2016 BIO International Convention, the world’s largest biotechnology gathering with over 900 speakers, 180 company presentations, 19 education tracks, 6 super sessions, and 35,000 partnering meetings. Now that’s a lot of stuff!

While many at BIO are focused on partnering – establishing new and exciting relationships with other biotech and pharmaceutical companies to push their products forward – others come to BIO to learn about the latest in research, innovation, and healthcare in the biotechnology space.

With so much going on at once, it’s hard to choose where to spend your time. If you follow BIO on twitter using the hashtag #BIO2016, you’ll get a condensed version of the who, what, and how of BIO.

For those of you who are more partial to blogs, here’s a brief recap of the talks that we’ve attended so far:

Mitochondrial Disease Education Session

A panel of scientific experts and patient advocates gave an overview of mitochondrial diseases and the latest research efforts to develop therapies for mitochondrial disease patients. Phil Yeske of the United Mitochondrial Disease Foundation described his foundation as the largest funder of mitochondrial research next to the government. Their focus is on patient-centered therapeutic development and they’ve established a community registry of patients that makes patients the central stewards for research and clinical development.

The most moving part of this session was an impromptu speech by Liz Kennerley, a mitochondrial disease patient and advocate. She bravely spoke about the roller coaster of symptoms affecting all of the organs in her body and aptly described her daily experience by quoting Forest Gump, “Life is like a box of chocolates, you never know what you’re gonna get.” She ended with the powerful statement that patients are at the core of everything scientists do, and encouraged the panel to engage patients more often because they will tell you everything if you ask them the right questions.

Mitochondrial Disease Patient Liz Kennerley.

Mitochondrial Disease Patient Liz Kennerley speaks at BIO 2016.

Moving out of Stealth Mode: Biotech journalists offer real-world advice on working with media to tell your story

One of my favorite panels of the conference so far featured three biotech journalists, Christina Farr of Fast Company, Jeff Cranmer of BioCentury, and Alex Lash of Xconomy. It was a dynamic conversation about how biotech companies coming out of stealth mode can best pitch their story to the media. Take home points include:

  • When pitching to a journalist, make sure that you are honest about what you can and can’t say. Have a “BS committee” that can address the validity of your work and your research claims.
  • When pitching, journalists want to know what the problem is you’re trying to solve and how you are trying to solve it better than anyone else.
  • On press releases: Unless it’s a press release from a big name, journalists won’t read it. The panel said they would prefer a personalized email detailing a company’s background and stage of work. They would also consider reading a press release that included a short personalized email from the company CEO.
  • Most hated words used to describe research: “Revolutionary” “Game-changing” “Disruptive”.

    Biotech journalist panel with.

    Moderator Carin Canale-Theakston with biotech journalists Jeff Cranmer, Alex Lash, and Christina Farr

Fireside Chat with University of California President Janet Napolitano

In an intimate Fireside chat, Janet Napolitano described her passion for higher education and making a difference in students’ lives. In her new role as the President of the UC system, her main focus is on aligning the policies and initiatives between the UC campuses and promoting research and innovation that can be commercialized around the world.

When asked about how she values basic research compared to applied research, Napolitano responded,

UC President Janet Napolitano

UC President Janet Napolitano

“We want an atmosphere where basic research is supported and one where innovation and entrepreneurship is fostered through incubators and public/private partnerships. We need to make these a tangible reality.”

 

Napolitano also mentioned that the UC system needs support from the private sector and gave PrimeUC – a collaboration with Johnson & Johnson Innovation that is part of her innovation and entrepreneurship initiative – as an example of a step in the right direction. You can read more about PrimeUC in this Event Recap.

From Ebola to Zika, how can we go faster in a global emergency?

I was only able to sit in on part of this expert panel, but here is the gist of their conversation. The global number of human infectious diseases is rapidly increasing every year due to hard-to-control factors like overpopulation, deforestation, and global climate change.  As a result, we’ve had two global health emergencies in the past two years: Ebola and Zika. We were more prepared to deal with the Ebola epidemic because more treatments were already in development. Unfortunately, we weren’t as prepared for Zika as it wasn’t on the world’s radar as a serious disease until 2015.

Martin Friede of the World Health Organization (WHO) said we should take what we learned from the recent Ebola outbreak and apply it to the Zika threat. He said the WHO wants to plan ahead for future outbreaks and remove bottlenecks to health benefits. They want to predict what diseases might surface in the future and have products ready for approval by the time those diseases manifest.


That’s all for now, but be sure to read Part 2 of our BIO2016 coverage tomorrow on the Stem Cellar. We will give highlights from an entertaining and fascinating Keynote address with Dr. Bennet Omalu (the doctor who blew the whistle on concussion in the NFL) and Oscar-nominated actor Will Smith (who played Dr. Omalu in the movie “Concussion”) on “Knowledge precipitates Evolution”. I’ll also tell you about an eye-opening Fireside chat with the US Food and Drug Administration Commissioner Robert Califf, and much more!

Shedding Light on a Path to Halting Deadly Pancreatic Cancers

Pancreatic cancer has a dismal prognosis: only a quarter of those diagnosed survive past one year and only about six percent live beyond five years. Its strong resistance to chemotherapy makes pancreatic cancer one of the most aggressive, deadly cancers and leaves doctors with few treatment options. New ways to study pancreatic cancer are desperately needed to find novel therapies.

Today, UCSD researchers, funded in part by CIRM, report in Nature on the development of a live imaging technique that enables precise tracking of drug resistant cancer stem cells within a pancreatic tumor. Using this method, they establish that the function of a gene called Musashi (Msi) is crucial for tumor growth, making it a promising target for chemotherapy drug development.

pancreatic_cancer_imaging

Activity of stem cell gene Musashi in human pancreatic cancer. Cancer cells are shown in green, Musashi expression in red and blue includes cells within the cancer microenvironment. Image courtesy of Dawn Jaquish, UC San Diego.

The Msi protein normally plays a role in the maintenance of stem cells but it’s also known to help sustain the growth of blood cancers. The UCSD team chose to investigate the role of Msi in pancreatic cancer as they found Msi was present in every human tumor sample they tested. To track Msi in a living animal, they genetically engineered mice that would emit fluorescence in cells where the Msi gene was activated.

Cells expressing the stem cell gene Musashi (green) are shown among other tumor cells (blue) and blood vessels (pink). Musashi-expressing cells preferentially drive tumor growth, drug resistance and lethality. UCSD

Those Msi mice were then bred with another strain of mice that mimic the pancreatic cancer seen in humans. In the resulting mice, cells with a strong fluorescent signal (indicating a high level of Msi) were found as a rare, distinct population in pancreatic cancer cells. It turns out that cancer stem cells, the cells thought to be responsible for cancerous growth and treatment relapse, are also known to make up a tiny portion of a tumor. So then, do Msi-positive cancer cells have cancer stem cell-like behavior? The answer appears to be “yes”. When the team transplanted the cancer cells with high levels of Msi from one mouse into the pancreas of healthy mice, every mouse tested died from very aggressive tumor growth. On the other hand, mice transplanted with cancer cells lacking the Msi fluorescent signal showed no evidence of disease.

These very promising results, along with the new imaging toolset, not only bode well for future treatments of pancreatic cancer but also for the cancer field as a whole. In a university press release, principal investigator Tannishtha Reya detailed this point:

pancreaticTannishtha Reya

Tannishtha Reya

“Because Msi reporter [fluorescence] activity can be visualized by live imaging, these models can be used to track cancer stem cells within the tumor microenvironment, providing a real-time view of cancer growth and metastasis, and serving as a platform to test new drugs that may be better able to eradicate resistant cells.”

Let’s hope that this research path leads to the day that a pancreatic cancer diagnosis isn’t an almost certain death sentence.

Good from bad: UCSF scientists turn scar-forming cells into healthy liver cells

Most people know that a healthy liver is key for survival. Unfortunately, maintaining a healthy liver isn’t always easy. There are more than 100 different types of liver disease caused by various factors like viral infection, obesity, and genetics. If left untreated, they can progress to end-stage liver disease, also known as cirrhosis, which effects more than 600,000 Americans and has a high mortality rate. While there is a cure in the form of liver transplantation, there aren’t enough healthy donors available to help out the number of patients who desperately need new livers.

Cirrhosis occurs when liver damage accumulates over time causing the development of scar tissue that eventually replaces healthy liver tissue and impairs liver function. The liver is an amazing organ and can function even with the build-up of scar tissue as long as at least 20% of its composition is healthy cells. This impressive nature is actually a problem because most patients with liver disease aren’t aware of their condition until its progressed past the point of no return.

What’s a damaged liver to do?

So what do patients with end-stage liver disease do if they can’t get a liver transplant? One answer comes in the form of regenerative medicine. Scientists can generate new healthy liver cells in a dish from stem cells derived from the skin cells of patients and could eventually transplant these cells into the damaged liver. However, a major roadblock that prevents this type of cell transplantation therapy from helping patients with liver disease is the built-up scar tissue that prevents the integration of these healthy cells into the damaged liver.

Scientists from UC San Francisco (UCSF) have come up with a new solution to this problem. In a CIRM-funded study published today in journal Cell Stem Cell, UCSF professor Holger Willenbring details a new approach to repairing damaged livers in mice – one that generates good, healthy liver cells from bad, scar-tissue forming cells already present in the damaged liver.

The bad cells in this case are called myofibroblasts. Initially, these cells play an important role in repairing injuries in the liver. They secrete proteins called collagen that form a support structure that helps maintain composition of the liver as it repairs itself. However, if liver damage persists as is the case with chronic injury, the excess buildup of collagen secreted by myofibroblasts causes the accumulation of permanent scar tissue or fibrosis, which can negatively impact liver function.

Reducing damage by improving function

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

In an “Ah-Ha” moment, Willenbring proposed that they could stop myofibroblasts in the damaged livers of mice from causing more fibrosis by turning them into healthy liver cells. Willenbring and his team used a specific type of virus called an adeno-associated virus that only infects myofibroblasts to deliver a cocktail of liver-specific genes that have the ability to transform cells into liver cells called hepatocytes. When they treated mice with end-stage liver disease with their viral cocktail, they observed that a small percentage of myofibroblasts were converted into hepatocytes that developed into new healthy liver tissue, which improved the overall liver function of these mice. They also tested their viral method on human myofibroblasts and found that it was successful in converting these cells into functional hepatocytes.

Willenbring explained the science behind their new technique in a UCSF news release:

“Part of why this works is that the liver is a naturally regenerative organ, so it can deal with new cells very well. What we see is that the converted cells are not only functionally integrated in the liver tissue, but also divide and expand, leading to patches of new liver tissue.”

Solution to a healthy liver?

It’s important to realize that these studies are still in their early stages. The UCSF team has plans to expand on their human cell studies and to improve their viral delivery method so that it is more specific to myofibroblasts and more efficient at converting these cells into functioning hepatocytes.

They also recognize that their strategy will not be the panacea for liver disease and cirrhosis. Willenbring commented:

“A liver transplant is still the best cure. This is more of a patch. But if it can boost liver function by just a couple percent, that can hopefully keep patients’ liver function over that critical threshold, and that could translate to decades more of life.”

However, their study does offer a number of advantages over cell transplant therapies for liver disease including repairing the liver and improving its function from within the organ itself and also offering a simpler and cheaper form of treatment that would be accessible to more patients.

Willenbring puts it best:

Holger Willenbring, UCSF

Holger Willenbring, UCSF

“The new results suggest that in the fibrotic liver, this approach could produce a more efficient and stable improvement of liver function than cell transplant approaches. Once the viral packaging is optimized, such a treatment could be done cheaply at a broad range of medical facilities, not just in the specialized research hospitals where stem-cell transplants could be conducted.”

Get your BIO on: Sneak Peak of the June 2016 BIO Convention in SF

Screen Shot 2016-06-01 at 8.43.36 AM

Summer is almost here and for scientists around the world, that means it’s time to flock to one of the world’s biggest biotech meetings, the BIO International Convention.

This year, BIO is hosted in the lovely city of San Francisco. From June 6-9th, over 15,000 biotechnology and pharma leaders, as well as other professionals, academics, and patients will congregate to learn, educate, and network.

There’s something for everyone at this convention. If you check out the BIO agenda, you’ll find a plethora of talks, events, education sessions, and fire side chats on almost any topic related to science and biotechnology that you can imagine. The hard part will be deciding what to attend in only four short days.

For those going to BIO this year, make sure to check out the myBIO event planning tool that’s free for attendees and allows you to browse events and create a personalized agenda. You can also set up a professional profile that will share your background and networking interests with others at BIO. With this nifty tool, you can search for scientists, companies, and speakers you might want to connect with during the convention. Think of all the potential networking opportunities right at your fingertips!

Will Smith (source)

Will Smith (source)

For those who can’t make it to BIO, don’t worry, we have you covered. CIRM will be at the convention blogging and live tweeting. Because our mission is to bring stem cell treatments to patients with unmet medical needs, the majority of our coverage will be on talks and sessions related to regenerative medicine and patient advocacy. However, there are definitely some sessions outside these areas that we won’t want to miss such as the Tuesday Keynote talk by Dr. Bennet Omalu – who helped reveal the extent of brain damage in the NFL – and actor Will Smith – who plays Dr. Omalu in the movie ‘Concussion’. Their join talk is called “Knowledge Precipitates Evolution.”

Here’s a sneak peak of some of the other talks and events that we think will be especially interesting:


Monday June 6th

Education Sessions on Brain Health and Mitochondrial Disease

Moving Out of Stealth Mode: Biotech Journalists Offer Real-World Advice on Working with Media to Tell Your Story

“In this interactive panel discussion, well-known biotech reporters from print and online outlets will share their insights on how to successfully work with the media. Session attendees will learn critical needs of the media from what makes a story newsworthy to how to “pitch” a reporter to strategies for translating complicated science into a story for a broad audience.”

The Bioethics of Drug Development: You Decide

A discussion of the critical bioethical issues innovative manufacturers face in today’s healthcare ecosystem. Panelists will provide insights from a diverse set of perspectives, including investors, the patient advocacy community, bioethicists and federal regulators.”


Tuesday June 7th

Fireside Chat with Robert Califf, Commissioner of the US Food and Drug Administration (FDA)

Fireside Chat with Janet Napolitano, President of the University of California

Casting a Wider Net in Alzheimer’s Research: The Diversity of Today’s Approaches and Signs of Progress

Hear clinical researchers, biotech CEOs, and patient advocates explain how the field is pivoting from the failures of past approaches to make use of the latest generation of beta-amyloid research results as well as pursue alternative therapeutic angles to improve brain health.”

From Ebola to Zika: How Can We Go Faster in a Global Emergency?

This interactive panel of public health and industry leaders will discuss what has been learned through our global response to Ebola and what is and is not applicable to Zika or other pathogens of pandemic potential.”


Wednesday June 8th

Curative Therapies: Aligning Policy with Science to Ensure Patient Access

“The promise of curative treatments creates an urgent need to ensure access for patients, promote an environment conducive to developing new treatments, and manage the concentration of healthcare expenses in a sustainable manner.  A diverse set of panelists will tackle the tough questions around curative therapies and discern what changes are necessary for our health care delivery system to meet the challenges they pose.”

An Evolving Paradigm: Advancing the Science of Patient Input in the Drug Development and Regulatory Processes

This panel will explore advances in the field of assessing patient views and perspectives, and highlight how the patient voice is being incorporated into development programs and informing FDA review and approval decisions.”

A Media Perspective

“Any press is good press or so they say. You want your story known at the right time and in the right light, but how do you get industry journalist to notice you? What peaks their interest and how do they go about story discovery? What will they be looking to write about in the next 3 to 12 months? Three top journalists will discuss their approaches to keeping current and what makes a story newsworthy.”
Patient Advocacy Meetup

Over 40 patient advocacy organizations will be discussing their latest partnerships and developments in the areas of advancing disease research and drug development.


Thursday June 9th

Novel Advances in Cancer R&D: Meeting the Needs of the Patient

This panel will feature the views of patients and advocates, regulators, and companies who are working to change the way in which we diagnose and evaluate patients with cancer by better understanding the underlying biology of their disease.”


 To follow our coverage of BIO, visit our Stem Cellar Blog or follow us on Twitter at @CIRMNews.

Outsmarting cancer’s deadly tricks

Cancer cells are devious monsters that kill people by sabotaging normal cell functions toward a path of uncontrolled cell growth. Without an effective treatment, aggressive cancers can crowd out healthy tissue and ultimately cause organ failure and death. This devastation by design makes it seem as though a cancer cell has a mind of its own but in reality it’s all due to mindless mutations in DNA. Gaining a deep understanding of those mutations provides scientists with insights into the molecular mechanisms of cancer which can help pinpoint targets for potential cancer treatments.

A team at The Scripps Research Institute (TSRI) followed the trail of such a mutation in a gene called POT1. Today in Cell Reports the researchers, funded in part by CIRM, describe their identification of a novel mechanism for cancer progression in cells carrying the POT1 mutation and they also speculate on the development on a unique therapeutic strategy.

Chromosomes go to pot without POT1
The POT1 protein is one component of shelterin, a multi-protein structure that binds to and protects telomeres, a region of DNA found at the ends of chromosomes. The team found that when POT1’s function is disrupted by mutation, the telomeres become vulnerable to damage which leads to chromosome instability. As a result, many regions of DNA on the chromosomes get rearranged leading to further gene mutations that in turn can accelerate the process of cancerous growth.

Telomere_caps

Human chromosomes (grey) capped by telomeres (white) Wikipedia

However, in the case of POT1 mutations, the DNA damage in the unstable chromosomes stimulates an enzyme called ATR that’s known to shut down cell division and initiate apoptosis, or programmed cell death. Now, unless I’m missing something, cells that have either stopped dividing or even died would seem to be the opposite of cancer progression. So why then are POT1 mutations found in a number of cancers such as leukemia, melanoma (skin cancer) and glioma (brain cancer)? As TSRI Associate Professor Eros Lazzerini Denchi, a co-leader on the publication, mentions in a press release, this conundrum presented an opportunity to better understand POT1 related cancers:

lazzerini_denchi

Eros Lazzerini Denchi

“Somehow those cells found a way to survive—and thrive. We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”

 

Mutant POT1 and p53: diabolical partners in cancer progression
The team looked for answers by studying the POT1 mutation in the presence of a mutated form of the p53 tumor suppressor gene, found in over 50% of all human cancers. Mice bred with the POT1 mutation alone formed no cancers while those animals with the p53 mutation alone developed T cell lymphomas, a type of immune system cancer, by 20 weeks and survived 24 weeks. Mice with both mutations fared much worse with median survival times of just 17 weeks. So somehow the p53 mutation was bringing out the potential of the POT1 mutation to cause aggressive cancer growth.

Further experiments revealed that the p53 mutation quashed the ATR enyzme’s programmed cell death signal which the team had shown was stimulated by the POT1 mutation. As a result, the cells avoided programmed cell death. Because the cells had no mechanism to die, more cancer-causing mutations had the opportunity to develop from the chromosome instability caused by the POT1 mutation.

The bright side to this diabolical cooperation between mutant POT1 and p53 is that it presents a possible opening for new treatment strategies. It turns out that no cell, not even a cancerous one, can survive in the complete absence of ATF. Since cells with the POT1 mutations already have a reduced level of ATF, the authors suggest that delivery of low doses of ATF inhibitors, which have already been developed for the clinic, could kill cancer cells without affecting healthy cells. No doubt the team is eager to follow up on this hypothesis.

It’s comforting to know that there are crafty scientists out there who are closing in on ways to outsmart the sneaky tactics of cancer cells. And it wouldn’t be possible without this fundamental research, as Lazzerini Denchi points out:

“This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer.”