Thursday, January 30, 2014

For my benefit

This post is for my benefit.  You may want to skip over it.

Due to the current funding environment, my job is a bit more stressful than I originally anticipated.  I am what is know in the business as a "triple threat": researcher, clinician, teacher. "Triple threats" may be a dying breed; there is some debate about that.  I have a lot on my plate. I don't claim to be alone or exceptional in that regard.

Things I need to remember when I feel stressed or when I am stewing over some job-related issue (if I sound like Stuart Smalley, I didn't intend it) :

It's too easy to focus on the "minus" column and overlook the pluses.

I am at home in two different worlds: I can function in a basic research environment as well as any PhD, and I can walk into a hospital or medical clinic and be mistaken for a pure clinician. MD-PhDs are plentiful at top medical schools. It is easy to forget that being both a fully qualified MD and a PhD-level researcher might be seen as impressive outside the medical school campus.  At least my parents are impressed.

Being a physician is a pretty big responsibility. Hey, some people do it full time and even make a career of it. I guess I should keep this in mind when I compare myself to straight basic research PhDs.

I can help diagnose and treat people who are ill. I am privileged to be able to do so. This also greatly helps in framing research questions.

David Brooks says " . . .  I tell kids if you have a great career and a crappy marriage, you will be miserable. If you have a crappy career and a great marriage, you’ll be happy."  I have a good marriage (to the fetching Mrs. Grantslave). I should count myself lucky.

I don't think my kids are going to laying on a psychiatrist's couch when they're adults and complaining about me.  I've been fortunate to have had the desire and the  flexibility in scheduling to be an involved, not bad father.  When I'm very old, I think I would have regretted the time I didn't spend with my kids more than the one extra grant application I didn't have time to write.

I have made contributions to our encyclopedia of knowledge about how the body works. For some reason, this is satisfying.  I have to remind myself that this is something I very much wanted to do when I was a naive kid.

Every predoctoral trainee that has come through my laboratory--both graduate students and students spending a couple of years in the lab before going to medical school--has had solid first-author papers.  This has not been the case with other, bigger, better funded laboratories that I am familiar with.

I have used the public's money efficiently and always keep in mind that I am spending tax dollars taken from the earnings of the supermarket manager just barely in the middle class or the tow truck driver just scraping by or spending funds donated by the earnest, well-meaning walk-a-thon participant.

I just looked at the blog CaliforniaStemCellReport, so I have to throw this in:
I have never and would never personally fight for the passage of a state proposition that would force residents of my state to pay specifically for my research, willingly or not. I would not grossly exaggerate the potential for near-term benefits of my research in order to influence 55% the residents of my state to vote for a law that would also forcibly extract money (as bonds are paid off) from the other 45% who perhaps felt they had better uses for their money.  Public funding of biomedical research is essential. I am strongly in favor.  But  I wouldn't become a huckster in order to coerce funding targeted specifically to my laboratory, which of course I think is highly valuable and meritorious of funding.

Saturday, January 25, 2014

Update to: Taking the "R" out of CIRM: is the stem cell agency acting lawfully?

David Jensen is a retired journalist who writes, pro bono, the California Stem Cell Report, a website that makes an important contribution to the monitoring of CIRM.  He is commendably even-handed; it's admirable that he takes time out of his active retirement to provide this service.

Mr. Jensen has written that he "expects to post an item dealing with the significant issues that our anonymous reader has raised."  I hope he finds the time to do this.  He is known at CIRM, so I imagine they'll be responsive to his queries. If he follows-up on this, I'll update this post accordingly.

Friday, January 10, 2014

"Academic bigotry"

Whenever I go to major scientific conferences, I'm always impressed by how well-represented Israel is. I have to stop and remind myself that Israel is tiny nation with a population of 8 million,  less than half of that of the greater Los Angeles metropolitan area. It's really amazing. Walk through the posters, go to the oral presentations: not only is Israel very well represented in quantity, but also quality. I don't like to generalize, but here goes: the Israeli scientists I meet are generally very talented and, equally important, they are nice, down to earth people. In terms of its contributions to science and medicine, including the number of Nobel prize winners who are connected in some way to Israel, the nation is pulling vastly more than its own weight, to the great benefit of all of us. Indeed, an immediate family member of mine who I feared would have been in a wheelchair years ago is still walking and active thanks to a medicine for MS developed in Israel.

I am fortunate to currently have a collaborator in Israel who has taken some of my findings and run with them, producing (so-far) exciting results that could, we hope, have a therapeutic application and help treat a major disease (although, as I have discussed previously, the odds of any particular therapeutic idea actually even making it as far as phase 1 trials--let alone into the clinic--are extremely low).

I don't know whether to be embarrassed or sickened or both by a small but vocal group of university faculty members--primarily in the humanities (which unsurprisingly is beset by a number of self-inflicted problems, including drastically falling numbers of undergraduates majoring in their area)--who, hopping from one trendy cause to the next, are now currently intent on badgering and trying to undermine the economy and safety of this small country surrounded by dysfunctional, violence-prone nations and by terrorist groups with truly genocidal intentions. They remain completely unable to provide a rational reason why, of all the nations in the world, they are singling out this one. Many people oppose the boycott idea on grounds that it is incompatible with academic freedom and the exchange of ideas. That is a valid reason, but there are other, more important and profound reasons to be disturbed by what these anti-Israel academics are up to. As Larry Summers put it, these boycott resolutions are  “anti-Semitic in their effect if not necessarily in their intent."

I wish my writing were anywhere near as crisp and lucid as Charles Krauthammer's:
". . . the ASA boycott has nothing to do with human rights. It’s an exercise in radical chic, giving marginalized academics a frisson of pretend anti-colonialism, seasoned with a dose of edgy anti-Semitism."

Tuesday, January 7, 2014

CIRM fought the California Legislature to keep the two-thirds vote requirement for funding non-stem-cell science. Said it was standing up for the will of the California voters.

The following points were made in my prior posts regarding CIRM:
  • First, if CIRM asks to raise more money via a new bond issue, they should not restrict grant awards made with the new funding to stem cell research (i.e., the law should be revised; with the new funding initiative, CIRM should transition into CIBR: California Institute for Biomedical Research). This makes obvious sense in light of the fact that  federal restrictions on embryonic stem cell funding have been lifted. (For the record, it is not GrantSlave's intention here to advocate for a continuation of CIRM in any form, even if it were to transition to CIBR.).
  • Second, CIRM is blatantly disregarding the intent of the law that brought it into being by funding non-stem-cell, non-regenerative medicine projects. Furthermore, there is no public record (that I have been able to find) that CIRM grant reviewers are deliberating whether these non-stem cell projects constitute "vital research opportunities" that merit funding despite being outside the intended scope of the law. The grant reviewers are legally required to vote on whether non-stem cell projects are "vital research opportunities" before these projects can be funded. A two-thirds super-majority is mandatory in order for funding to be approved.
In 2008, the California Senate passed SB 1565 amending the law underlying CIRM by a vote of 40-0. The bill won in the assembly 64-7. This bill would have made it easier to fund non-stem-cell science, something I advocated in my first post. It was vetoed by Governor Schwarzenegger and never saw the light of day again.

CIRM opposed SB 1565. They wanted to keep the two-thirds vote requirement for non-stem-cell research. They felt it was important. Here is what the CIRM leadership had to say (emphasis not mine--underlining and bolding from their letter):

  •  ". . . the proposed amendment to Proposition 71 would send the wrong message to Californians and to the nation at largeIt would also thwart the will of the more than seven million Californians who voted for Proposition 71 in order to address the federal funding gap for human embryonic stem cell research, a gap that continues to exist to this day. By removing the two-thirds vote requirement, the amendment would undermine the very purpose of Proposition 71 – to provide a priority for funding human embryonic stem cell research. . . . For all of these reasons . . . we are strongly opposed to the removal of the two-thirds vote requirement."
So, the will of the California people was to fund embryonic stem cell research? OK, the feds have lifted their restrictions, so we can excuse CIRM's funding of other, non-embyronic, stem cell research. This other stem-cell research is, after all, allowed in the underlying law. 

But what about all the funding of non-stem cell, non-regenerative medicine projects? What happened to standing up for the will of the more than 7 million Californians who voted for Prop 71? And what about this very important two-thirds vote requirement for funding non-stem-cell research? Is deliberating whether non-stem-cell projects are "vital research interests" no longer important? There no mention of such deliberations or the legally mandated votes in the detailed review summaries generated for funded grants: see, for example this summary of an awarded, non-stem cell grant. CIRM fought to keep the requirement for these two-thirds votes in place: is it not important to at least document for the public that they have occurred?  My guess is that they are not taking place: if they were, the discussions and outcomes would most likely be included in the review summaries.

(note: post revised for clarity)

Friday, January 3, 2014

Taking the "R" out of CIRM: is the stem cell agency acting lawfully?

The California Institute for Regenerative Medicine (CIRM) was brought into existence by the passage of Proposition 71. Note the word "Regenerative." It is essential to understanding the intent of Prop 71 and how it was sold to the voters. The name of the agency was not an afterthought: it was stipulated in the first sentence of the enabling constitutional amendment: "There is hereby established the California Institute for Regenerative Medicine."

Proposition 71 was meant to promote research using stem cells, most significantly human embryonic stem cells. Stem cells can be employed in biomedical research in different ways. The most exciting and most heavily-promoted potential application was (and is) using these cells to regrow or create replacement tissue for damaged organs or nerves: to "regenerate" these tissues. Here is how the argument that was put forward in favor of Prop 71 in the official voter information guide begins: "stem cells are unique cells that generate healthy new cells, tissues, and organs. Medical researchers believe stem cell research could lead to treatments and cures for many diseases and injuries . . . ."

Now let's look at the intent of Prop 71 as spelled out within the actual text of the law. From the Findings and Declarations: "the California Stem Cell Research and Cures Act will  . . . [establish] an institute which will issue bonds to support stem cell research, emphasizing pluripotent stem cell and progenitor cell research and other vital medical technologies, for the development of life-saving regenerative medical treatments and cures" (emphasis mine).

In short, the intent of Proposition 71 was crystal clear. Californians agreed to pay for stem cell research and especially the development of  "regenerative medical treatments and cures." Why, then, has CIRM awarded almost $100 million for relatively conventional, non-stem-cell cancer research? Is this because the stem cell program has so far failed to yield new therapies? Is CIRM is so eager to make good on its promises that it's willingly ignoring the intent of the law that created it?

You can find the words "stem cells" in the titles and the abstracts of the cancer research to which I'm referring, but don't be fooled. Cancer stem cells are not the stem cells or pluripotent/progenitor cells referred to in the law or in the advertising for Prop 71. Cancer stem cells can have some of the same characteristics and molecular properties as stem cells and they may perhaps arise from normal progenitor cells, but they are abnormal and, unlike stem cells, cannot form normal tissues: rather, they yield malignancies and are thought to underlie disease relapses. They have no use in regenerative medicine. Research into cancer stem cells is conventional in several senses. First, as has always been the case with cancer, the goal is to find therapies to kill the malignant cells or at least get them to stop dividing--for example by inhibiting enzymes called kinases or targeting proteins on their surface--while leaving normal cells as unperturbed as possible. This type of research is widespread in academia, pharma and biotech and has never been subject to federal restrictions. The NIH has been funding research involving cancer stem cells since at least 1999. Of note, Iriving Weissmann, a big proponent of Prop 71 and recipient of Prop 71 funds for cancer stem cell research (most recently a nearly $13 million award focused on leukemia), has been receiving NIH funding for research into cancer stem cell-related therapies since at least 2009.

Funding of cancer stem cell therapy is not aligned with the intent of the law and has never been subject to NIH restrictions. Adult stem cells, stem cells, progenitor cells and pluripotent cells--the cell types that are are the focus of the law--are defined in Article 3. Cancer stem cells do not fall under any of these categories.

Now delving further into the letter of the law: consistent with law's intent, the section describing how research funding is to be awarded stipulates that "a high priority shall be placed on funding pluripotent stem cell and progenitor cell research that cannot, or is unlikely to, receive timely or sufficient federal funding, unencumbered by limitations that would impede the research. In this regard, other research categories funded by the National Institutes of Health shall not be funded by the institute." Cancer stem cell research is not pluripotent stem cell or progenitor cell research, there are no restrictions on cancer stem cell funding, and the NIH has funded many grants looking at cancer stem cells in one way or another.

A provision of the law allows non stem-cell research to be funded  "if at least two-thirds of a quorum of the members of the Scientific and Medical Research Funding Working Group recommend to the ICOC that such a research proposal is a vital research opportunity." The Review Summaries from the Scientific and Medical Research Funding Working Group are available online (e.g., see here). There is no indication that consideration was given to the fact that the projects are outside the intended scope of the law nor is there reasoning provided why they should nevertheless be funded as "vital research opportunities."  Of equal importance, there is no indication that the required separate votes were taken and resulted in the stipulated two-thirds super-majorities.

In the latest funding announcement from CIRM, half of the awarded applications and approximately half of the $60 million in awarded funds went to such non-stem cell (cancer stem cell) projects. Other projects within the intended research scope of the law were passed over.

CIRM, perhaps feeling pressure to live up to its initial hype, seems to be disregarding the intent of Prop 71 (as spelled out within the law itself).

Unless the required votes are being taken recommending the cancer stem cell projects as "vital research opportunities," CIRM may be operating unlawfully. I am unable to find any mention of these votes and the required two-thirds outcomes in the publicly-available documents on the CIRM website. I do not understand how, if these procedures are not being followed, CIRM can be said to be acting in a lawful manner.

Should CIRM be backing away from the riskier, much less further advanced stem cell research it was created to advance in favor of cancer research? Should we expect CIRM to adhere at least to the letter of the law if not the intent?

UPDATE: more on the two-thirds vote requirement in my next post.

ANOTHER UPDATE: David Jensen may look into these issues.