California CRISPR: Three Golden State Researchers Slated to Explore Gene Editing Directions

Three California stem cell researchers are on tap this week to discuss current and future projects that could involve the state's $3 billion stem cell research agency, CRISPR concerns and the possibility of scientific missteps or worse.

The trio is scheduled to speak at a day-long conference Thursday in Los Angeles which has been convened by the California Institute for Regenerative Medicine (CIRM), as the agency is formally known.

The CRISPR technique allows relatively easy changes in genes, including alterations that could be inherited and become part of the human race.

The possibilities have stirred concern internationally, leading many blue-ribbon scientists to call for a moratorium on use of the technique in some cases.

CIRM has promised a full array of bioethicists and others for its conclave. Specifically scheduled to explore research directions in California are Jacob Corn, managing director and scientific director of the Innovative Genomics Initiative at UC Berkeley; Amander Clark, professor and vice chair of the Department of Molecular, Cell and Developmental Biology at UCLA, and Juan Carlos Izpisua Belmonte of the Salk Institute and former director of the Center for Regenerative Medicine in Barcelona.

Clark and Izpisua Belmonte are both recipients of awards from the California stem cell agency.

Juan Carlos Izpisua Belmonte
Salk photo

Izpisua Belmonte has received three CIRM grants totaling $6.6 million, one of which deals with vascular disease. He filed a progress report on the research that said, 

“During the course of this project we have been able to identify novel genetic elements and laboratory conditions facilitating the conversion of human skin cells to vessels comprising the vascular system. The generation of vessels in the laboratory may allow for the treatment of multiple human maladies including ischemic situations.”

Clark received a $1.2 million award from CIRM dealing with human embryonic stem cells. Her CIRM progress report said that the research resulted in development of 15 new hESC lines and will help improve understanding of Down Syndrome.

Amander Clark, UCLA photo

Corn is closely connected to Jennifer Doudna, who is executive director of Berkeley’s Innovative Genomics Initiative. Doudna developed the CRISPR technique at her lab at Berkeley. 

Jacob Corn, UC Berkeley photo

Last month, Corn provided a “translation” of the statement from the widely publicized international conference in December on human gene editing.

Corn wrote, at one point, that the document said “trans-generational gene editing could be very unfair, and might extend ‘rich get richer’ societal problems into our very genes, and trans-generational edits could change our own evolution more than societal influences, and it’s not clear that we actually want to or should do that.”

In addition to the public session in Los Angeles, Thursday's meeting will be available via an audiocast. Directions are on the agenda, but allow some time in advance for setting up your access.

Human Genetic Alteration and Gold Mines: California's Stem Cell Agency Takes a Hard Look at Research Standards

The $3 billion California stem cell agency next Thursday will convene a day-long examination of human gene editing, a field that could be a “gold mine for biotechnology” and perhaps alter the human race permanently.

“Easy DNA Editing Will Remake the World. Buckle Up.” is the way Wired magazine put it in a headline on a lengthy overview article last July.

The piece by Amy Waxmen said that gene editing has “already reversed mutations that cause blindness, stopped cancer cells from multiplying, and made cells impervious to the virus that causes AIDS.”

The key focus is on CRISPR, which is a technique developed at UC Berkeley and which is involved in substantial amounts of the research funded by the California stem cell agency. CRISPR, according to one description, makes changing genes as easy as cutting and pasting changes in this article.

The session next week at Los Angeles International Airport is chock-a-block with big names in

scientific research and ethics, including David Baltimore, a Nobel Prize winner, former president of Caltech and a former member of the stem cell agency board. At an international CRISPR

David Baltimore, Pasadena Now photo

 conclave in December, Baltimore said,

“The overriding question is when, if ever, we will want to use gene editing to change human inheritance.”

The New York Times reported that the group called for what would be, “in effect,” a moratorium on making inheritable changes to the human genome.

In addition to Baltimore, next week’s California conference is scheduled to hear from Alta Charo of the University of Wisconsin and a leading authority on bioethics; Hank Greely, a specialist in bioscience issues at Stanford law school; Jonathan Kimmelman, a bioethicist from Canada’s McGill University, and Charis Thompson, founding director of the Science,

Charis Thompson, UC Santa Cruz photo

Technology, and Society Center at UC Berkeley, along with a number of scientific researchers.

The agenda for the meeting states that the stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM), “will continue to support groundbreaking stem cell treatments and technologies, including gamete and embryo research, from their inception to translation.”

“In light of recent science-policy initiatives,” said the CIRM document, the agency’s research standards group has been asked to examine the agency’s policies dealing with human gene editing.

“One objective of this review is to ensure CIRM research continues to be conducted under the highest medical and ethical standards,” the agency said.

An upshot from next week’s meetings could well be changes in what is permitted to be done by the hundreds of researchers who have funding from the stem cell agency. Beyond that, decisions by the Golden State agency are likely to influence other funding agencies and researchers globally.

CIRM already has alliances with a number of countries, including China, Spain, Israel and Poland. And the agency is closely watched by many from outside California.

Many of the stem cell agency’s meetings of much less import are available live on the Internet. The meeting agenda initially did not list such access. The California Stem Cell Report earlier this week queried the agency about audiocast or Internet access to the session.

Kevin McCormack, senior director of communications, replied late today, 

“When it comes to CIRM, transparent is the new black. Yes, we will be having an audio feed for the standards working group on Feb 4th. Details will be posted on the website shortly.”

The agenda also has links to several useful background pieces along with the names of other invited participants.

A Book Review: Stem Cell Battles in California, a Pioneer's Perspective

(Editor's note: The following book review was offered by Raymond Barglow of Berkeley, who describes himself as a veteran of the Proposition 71 ballot campaign of 2004.) 

By Raymond Barglow

Don Reed's new book "Stem Cell Battles: Proposition 71 and Beyond" (available at Amazon) gives us an insider's perspective on the historical whirlwind that today is driving forward medical research in California and elsewhere. The author, who has been called the "Grandfather of Stem Cell Research Advocacy" for his longstanding commitment to this cause, is intimately familiar with the community of scientists, politicians, and patient activists who first came together over a decade ago to advocate stem cell research. Their signature achievement has been passage of Proposition 71 in California, which established financing for the research to the tune of three billion dollars. Largely as a result of their effort, we stand today at the threshold of medical breakthroughs that will save millions of lives.

As Reed explains, the stem cell research mission is advanced out not only in laboratories but also in the centers of political power. The research requires funding and has to withstand attack from

Don Reed on right, left is Bob Klein, former
 chairman of the stem cell agency,  and center is
Arnold Schwarzenegger, former governor of California

religious fanaticism that aims to shut it down. Standing staunchly against publicly funded embryonic stem cell research have been not only anti-government conservatives but also fundamentalist religious organizations and Catholic officialdom.

Claiming that the very earliest embryo, consisting of a few hundred cells and so small that it is invisible to the naked eye, has a sacred "right to life," opponents of embryonic stem cell research have organized to defeat funding in federal and state legislatures and have sued in court to make the research illegal. This has been and continues to be a hard-fought battle, with neither side clearly prevailing to date.

In the 1980s and '90s, AIDS activism united patient advocates with doctors and scientists to push forward the search for cures. Less well known is the stem cell research movement whose equally challenging path forward Reed chronicles for us. Although the story that he tells begins in California, many milestones have also been achieved in other states and abroad. Researchers in Canada, China, Singapore, Brazil, Japan and many other countries form a worldwide community to advance the search for deeper understanding of diseases and the invention of effective stem cell treatments to cure them. In a world torn apart by narrow interests and violent antagonisms, we have much to learn from the example of impassioned cooperation that the worldwide stem cell research community has set.

In brief, Don Reed provides in this book an inside view of the stem cell research saga, and he's done so with wisdom, spirit, and a sense of humor that combine to make the book entertaining as well as profoundly illuminating.

Plug Pulled on Cancer Clinical Trial: Sudden End for $18 Million Push by California Stem Cell Agency

Caladrius stock price plummets -- Google graphic

California’s ambitious, $18 million effort to develop -- in relatively short order -- a stem cell therapy for a deadly form of skin cancer collapsed abruptly last week, apparently the victim of “excessively long development timelines.”

Caladrius Biosciences, Inc., the recipient of the California funding, terminated the late stage clinical trial, declaring that other treatments have outpaced its approach and that it is no longer “optimally leverage(d).”

The award last May marked a big advance for California’s $3 billion stem cell research program. It was the first phase three clinical trial for the agency, known formally as the California Institute for Regenerative Medicine(CIRM).  A phase three clinical trial is the last step needed before federal approval for widespread use of a treatment. The award came as the agency is entering what could be the last years of its life and is pushing hard to fulfill the promises of the 2004 ballot initiative campaign that led to its creation.

CIRM, which is based in Oakland, Ca., is scheduled to run out of cash for new awards in 2020. The agency expects to intensify its efforts this year at developing a plan to replace the state bonds that it has used since 2004.

The $18 million award to Caladrius was made last spring with considerable ballyhoo. Jonathan Thomas, chairman of the agency’s governing board, said at the time that the  treatment had “the greatest chance of success for the people of California that we have funded.”

After the Caladrius announcement, Randy Mills, president of the agency, said in a news release,

“Ultimately this program suffered from the excessively long development timelines common in cell therapy, a fact that further underscores the need for CIRM to work hard to create faster development pathways as called for in our new strategic plan.”

CIRM’s statement also said,

“Only $3 million of the $17.7 million awarded by our governing board had been distributed to Caladrius, which matched that money with $3 million of its own. CIRM will now make the unused $14.7 million portion available to other applicants for investment into projects that accelerate stem cell therapies to patients with unmet medical needs.”

In a document filed with the Securities and Exchange Commission, Caladrius, formerly known as NeoStem, said the end of the trial would lead to layoffs for about 40 employees in Irvine, Ca., the home of what once was California Stem Cell, Inc. That firm was acquired by Caladrius in 2014 for $124 million. It  was founded by Hans Kierstead of UC Irvine, who is senior vice president for research and chief science officer of Caladrius.

The company’s SEC filing said,

“The treatment paradigm in metastatic melanoma was transformed during the course of 2015 by the accelerating adoption of multiple immune checkpoint inhibitors used as monotherapy and in combination treatments. These new drugs have significantly improved outcomes in metastatic melanoma and therefore have altered the opportunity for a monotherapy such as CLBS20 in a landscape that is quickly converting to combination therapies. Therefore, we have concluded that, as designed, our current program in metastatic melanoma will not optimally leverage this asset..."

Cancellation of the phase three trial led to a sharp drop in Caladrius’ stock price. It closed at $1.08 on Jan. 6, the day prior to the announcement. Today, the stock closed at 65 cents. The 52 week high for the stock was $4.26 and the low 40 cents. The chair of Caladrius, Robin Smith, resigned on Dec. 23.

California’s stem cell agency is now participating in only one phase three trial, which is not yet recruiting patients. That effort involves a brain tumor program with ImmunoCellular of Calabasas, Ca. The agency is currently participating in a total of  15 clinical trials at various stages.

California Stem Cell Agency Alters Grant Rules to Hasten and Improve Basic, Translational Research

A key committee of the governing board of the $3 billion California stem cell agency this morning approved changes in its grant rules in an effort to speed basic and translational research and attract higher quality applications.

The Science Subcommittee sent the changes to the full board on an 8-0 voice vote with no discussion and no public comment. The full board is expected to ratify the proposals at its Jan. 19 meeting.

The action came as the agency continued its new effort to provide more public access to important policy discussions and actions by the board's key committees. Today's meeting was accessible live on the Internet and by audiocast. For the past decade or so, only the meetings of the full board were available live on the Internet.

The new rules will cover hundreds of millions of dollars in awards for basic and translational research as well as educational training.  Hundreds of California researchers could be affected.

The proposals were based on earlier changes in clinical award rules. They are expected to strengthen the agency's ability to terminate research when milestones are not being met and establish a researcher's past performance on agency awards as a criteria for future funding. Also to be altered are rules about use of funds not spent during the award period.

The regulations are being enacted on an interim basis and will be subject to change as they wend their way through the official state regulation process.

Here is a staff memo on the rules and the full text of the agency's grant administration regulations. 

California Stem Cell Agency Opens Live Internet Access to Key Subcommittee Meetings for First Time in 12 Years

Highlights
Move Opens Door to More Public Participation
Major Policy Sessions to be Available
Tuesday Meeting Involves Hundreds of Millions in Grants

With no fanfare, California's $3 billion stem cell agency is making a significant step forward in openness and transparency regarding the dealings of its governing board, which operates outside of the control of the governor and legislature.

Next Tuesday’s meeting of the directors’ Science Subcommittee will be available live for the first time -- for all practical purposes -- on the Internet and as an audiocast, including access to presentations that are used at the meeting. The agency intends to allow public access for other directors' subcommittee meetings as well.

The move appears to be patterned after action by state Treasurer John Chiang, whose office holds many public meetings involving sometimes billions of dollars.  Last summer he added an audiocast feature to treasurer’s meetings.

A spokesman for the treasurer told the California Stem Cell Report last summer that Chiang wanted to enhance public access and to “increase public participation in and increase awareness of the many boards, commissions and authorities" that he chairs. The treasurer’s office said the cost was much less than $100 a session.

Tuesday’s stem cell audiocast follows procedures of the full board but never applied to other meetings of the California Institute for Regenerative Medicine, as the agency is formally known.

Last month, the stem cell agency attempted to provide an audiocast, which are also available for later listening, of a subcommittee meeting. However, the audiocast was not accessible for subsequent public use. The problem seemed to be a technical glitch because the agency said that it could be heard when CIRM staffers logged in.

Generally subcommittee meetings of the board rarely attract attendees from the public or the scientific community. However, major policy and scientific initiatives are discussed in more detail than at full board meetings. Suggestions for changes in proposals are more likely to be accepted in a subcommittee than at full board meetings, where proposals are ratified, usually without much discussion.

At next Tuesday’s meeting, for example, the Science Subcommittee is scheduled to act on new rules that will involve hundreds of millions of dollars in grants. Hundreds of California scientists engaged in basic and translational research as well as the progress of their efforts are likely to be affected. Educational training awards will also see new rules.

A memo to the subcommittee from Gabriel Thompson, director of grants management, said that the proposed rules are “designed to attract more high quality applications, reduce the cycle time from application to project start, accelerate progression of funded projects and provide for more efficient administration of the projects.”

One of the proposed changes appears to give the agency more power to pull the plug on research when it is not progressing satisfactorily by agency standards. The new rules would affect use of grant funds that are not spent by the end of the research. Past performance of grantees would also be established as a criteria for future funding.

Interested parties can find directions for logging into the Internet and audiocast on the meeting agenda. Some set-up may be required so it is best to check in advance the instructions on the agenda. 

The meeting will be based at the agency’s new headquarters in Oakland and is open to the public there. Teleconference locations where the public can speak to the committee as well as listen are available in Los Angeles and La Jolla. Addresses can be found on the agenda.

Readership Numbers for the Stem Cellar, the official blog of California's Stem Cell Agency

Here are some readership figures for the Stem Cellar, the official blog of the California stem cell agency, known formally as the California Institute for Regenerative Medicine.

The numbers and text were provided by the agency and come from Kevin McCormack, senior director of communications.

"We only have stats from May 2014 because that is the date when this blog was switched to Wordpress (that’s also the reason why the viewing figures for May were so low, it took people a while to find the new site). The blog started in 2007 on a site called blogspot." 

Data from 2015:

Home page views: 34,871

Top blog reads: 2,336

Best ever views: Sept 2^nd 2015 with 1,454 views

From May 2014-Dec 2015

Views went from 60  to ~13,000

	Jan	Feb	Mar	Apr	May	Jun	Jul	Aug	Sep	Oct	Nov	Dec	Total
2014					60	1,715	6,019	7,274	5,807	8,448	11,420	9,592	50,335
2015	11,045	8,664	10,383	7,520	9,326	10,344	8,303	10,010	13,230	13,634	13,391	12,145	127,995

Average per Day

	Jan	Feb	Mar	Apr	May	Jun	Jul	Aug	Sep	Oct	Nov	Dec	Overall
2014					2	57	194	235	194	273	381	309	209
2015	356	309	335	251	301	345	268	323	441	440	446	429	353

Referrers (in order of top views)

1)    Search Engines (google, bing, yahoo)

2)    Facebook

3)    Twitter

Total # Posts: 1,555

Total followers: 485 (115 on wordpress and 370 on email subscription)

(Editor's note: This item was belatedly added in September 2016 because of publishing error in January 2016, when it should have been posted by yours truly.)

The Stem Cellar Named the World's Best Stem Cell Blog: Compelling Content, Commentary and More

The blog of the $3 billion California stem cell agency last month was ranked as the best stem cell blog in the world by the only entity that measures such things. 

The designation came from The Niche, a stem cell blog published by UC Davis researcher Paul Knoepfler, who on Dec. 22 identified the best blogs in the field for 2015. He said,

“The (top) prize goes to CIRM’s The Stem Cellar. While this is a tough choice (see more below on other stem cell blogs), CIRM’s blog has continued from year to year to step up its game. They post very often, sometimes daily. Their posts are composed of compelling content that includes reports on papers and other developments, but also commentary. I really appreciate the latter and that is fairly unique. They have also gone well beyond just focusing on CIRM-related matters to include broader issues for the stem cell field.”

(CIRM is the acronym for the California Institute for Regenerative Medicine, the formal name of the agency.)

Knoepfler continued,

“...(F)inishing a close second was Alexey Bersenev’s blog StemCellAssays. It continues to be incredible. Alexey regularly posts on the more technical side of stem cells, regenerative medicine, cellular medicine, and more. StemCellAssays is a much read for those interested in this field from any number of angles."

Kevin McCormack, WAF photo

The California Stem Cell Report, which was on Knoepfler’s short list, asked the stem cell agency about its blog, its readership and how it operates. Kevin McCormack, senior director of communications, replied,

“It was very flattering obviously to learn that Paul had named us as the #1 stem cell blog. We’ve been working hard to make our blog as engaging and thoughtful, and fun, as possible and this was vindication that at least in his eyes we had succeeded.

“Our strategy is really quite simple. We look for what we think are the best, most interesting stories out there, and then write about them. Obviously we like to highlight stories about research we are funding but more often than not we’re just looking for something new, something fresh, something that sheds a new light on research in general or on tackling a particular disease or problem in particular.”

(For the full text of McCormack’s reply, see here.)

Todd Dubnicoff, CIRM photo

Karen Ring, CIRM photo

In addition to McCormack, three other CIRM team members write for The Stem Cellar, which posts virtually five days a week. They are Karen Ring, a former stem cell researcher, Don Gibbons and Todd Dubnicoff. The pace of postings is important because it is generally believed in the blogosphere that blogs must be fed often to keep readers interested.

Don Gibbons, CIRM photo

The activity on the blog has additional significance since CIRM’s home page is fundamentally static and rarely changes on a day-to-day basis. So the liveliness on the blog helps keep people coming back to the agency’s information where it touts its success. 

As for readership of the blog, it obviously draws attention from scientists and patients. But the audience is small compared to the mammoth numbers chalked up by big name blogs, which count their readership in millions. McCormack said WordPress reported 127,995 page views for 2015 for the agency’s blog. (For more numbers, see here.).

A Pew Research Center study reported last year that the number of scientists who are blogging is growing as awareness increases about the importance of making full use of Internet communications tools.

Susan Gunelius, writing on the ACI Information Group's Web site, said,

"Certainly, the more scientists who publish blogs and share their findings via social media, the more the public will learn about science from reputable sources. With that in mind, let’s hope that the number of scientists who are active on social media and writing blogs continues to grow!"

Here is the list of the other stem cell blogs rated highly by Knoepfler: the California Stem Cell Report,  EuroStemCell, ISSCR Blog, msemporda, Signals Blog, Stem Cell Assays, Stem Cell Podcast, Stem Cells Buzz, The Node.

Knoepfler, who has received grants from the California stem cell agency, reported that msemporda and Stem Cells Buzz are new to the game.

CIRM's Approach to Stem Cell Blogging: The Full Text

The California Stem Cell Report asked the California stem cell agency for a run down on how it approaches its blog, which in December was rated the top stem cell blog of 2015 by The Niche, another stem cell blog published by UC Davis researcher Paul Knoepfler.

Kevin McCormack, senior director for communications, replied,

"It was very flattering obviously to learn that Paul had named us as the #1 stem cell blog. We’ve been working hard to make our blog as engaging and thoughtful, and fun, as possible and this was vindication that at least in his eyes we had succeeded.

"Our is really quite simple. We look for what we think are the best, most interesting stories out there, and then write about them. Obviously we like to highlight stories about research we are funding but more often than not we’re just looking for something new, something fresh, something that sheds a new light on research in general or on tackling a particular disease or problem in particular.

"We try to divide it up so that we all write a blog every week, that way we get different voices and flavors in the mix. I think that’s important for a number of reasons. One, it creates a sense that this is truly a team blog, and two, it allows each of us to take a little bit more time in writing each piece, to make sure we get it right and to do it in a way that is most interesting and accessible for our audience.

"We have a really broad range of people reading us from researchers and scientists to people with no science background (like me), so we are always mindful of trying to write in a way that allows everyone to understand what’s going on. We also try to write in a way that reflects how exciting this research is and the potential it has. But we also try to balance that by reminding people that some of this work was done in animals and needs to be replicated in people before we get carried away.

"One of the new things that Dr. Karen Ring has added, since joining us this year, is more individual profiles of young researchers. These have been popular in helping give a voice to a group of people who are often overlooked, the youngest members of the research teams, the people who represent the future of stem cell research and are the next generation of scientific stars.

"We are always looking to add new ideas, new voices to the blog. So if you have any thoughts or ideas left over from your own, let us know. We’re happy to try anything. At least once."