Home stretch on October deadline NIH grant & I’m…(fill in the blank)

NIH logoGrant deadlines are no picnic.

Like thousands of scientists around the US, I too am working on a big NIH grant proposal due in a matter of a few days.

If you are also in this boat, how are you all feeling right now since it is October 1st?

How would you complete this sentence:

“I need to send off my NIH grant proposal soon for the October deadline & I’m…”?

Let us know in the comments.

Some things I’ve heard….

  • Drinking more coffee
  • Living in my office
  • Eating more chocolate
  • Fighting blurry vision from staring at the computer
  • Still wrestling with Aim 3
  • Not feeling my fingers anymore, which are numb from all that typing
  • Downing on energy drinks
  • Thinking again that grants should be submitted entirely in video form
  • Literally sick
  • Considering throwing my computer out the window
  • Already aware of what the reviewers will say, but there’s nothing I can do at this point
  • Starting on my grant(s) for the February deadline since I already submitted this one (damn you!)

 

These are your stem cells on drugs…any questions?

Brain on drugsHow do “drugs” influence stem cells?

Here’s the straight dope.

Those of us in the trenches of the stem cell research field spend an inordinate amount of time talking about stem cell treatments (i.e. you inject stem cells into a person hoping for a medical benefit), and far too little time discussing endogenous stem cells.

Endogenous stem cells are those little guys that we all have already inside of us. They crawl around and do good things. Sometimes they do bad things like turn into cancer stem cells.

I think it is a reasonable prediction that how we live our lives greatly affects those natural stem cells and in turn our health. I’ve blogged before about how to try to protect those little, but oh so important cells.

Today’s topic is how drug use affects our stem cells.

Some of the more interesting research on this question is focused on the brain. While for decades we all “knew” that the adult brain had no stem cells, turns out we were wrong. The brain has a limited number of stem cells and they are doing their stemmy stuff up there in our craniums even if scientists don’t totally understand why they are there. Weirdly, at least part of the point of us adults (if you can call us scientists that) having stem cells in our brains seem to be related to olfaction.

In that famous anti-drug commercial “This is your brain…this is your brain on drugs…any questions?” the brain is represented by eggs and drugs fry them.

So do drugs fry stem cells in our brains?

The jury is still out in some cases, while in others its pretty clear that drugs do fry stem cells.

Ethanol

Arguably the most popular drug, booze, is often cited (and I’ve said this myself to the students that I teach) as an effective way to nuke your brain cells. But is that really true and what about affecting stem cells in the brain or elsewhere?

A Pubmed search for articles having these 3 key words in the title (stem cells ethanol) surprisingly only yielded 25 articles in total. What the heck? However, even from these 25 papers it’s pretty clear that stem cells are sensitive to ethanol and change their behavior in response. But there isn’t much evidence to speak of at least in that search suggesting that ethanol in physiological doses is toxic to adult stem cells.

In contrast, there is compelling evidence that maternal consumption of alcohol is stemotoxic to the fetus, particularly to the fetal brain.

MDMA

One paper reported that MDMA (Ecstasy, Molly, X, 3,4-methylenedioxy-N-methylamphetamine) was not good for the rat brain, reducing stem cells and neurons.

In terms of embryonic stem cells (ESCs), MDMA  was reported to be toxic to cardiac and neural cells made from ESCs.

Another study, however, found that MDMA  slows proliferation of ESCs themselves, but actually promotes self-renewal (stem cells making more stem cells) without evident toxicity. At least in mice.

Pot/Cannabis

What’s up with pot and stem cells? Are high stem cells a good thing? Pubmed searches for THC and stem cells or marijuana and stem cells both yielded just under a couple dozen papers. The verdict? The high stem cells needed their media changed more often….but seriously, I would say these studies do not present a coherent case for how stem cells react to pot-related chemicals, but they sure do seem to react and some types of stem cells have cannabinoid receptors.

Opioids

There are more than 100 articles that mention stem cells and opioids. Who knew? But actually most of these are focused on something else. Only 8 articles have these words in their titles. Again, the take home message is foggy, but there seem to be some kinds of effects including on stem cell differentiation.

There are many other drugs, recreational or not, that certainly influence stem cells as well.

Stem cells on stem cells.

Of course the ultimate irony here is that stem cells themselves, produced as treatments for various ailments, are considered drugs.

 

Stem Cells, Nukes, & Bikini Experts

How are stem cells, nukes, and bikini experts connected?

Let’s go back in time a bit…

The idea of stem cells has been around more than a century. For example Dr. Artur Pappenheim made a cell fate tree including stem cells in 1905. You can read more about this amazing, more than 100-year old stem cell model in my book, Stem Cells: An Insider’s Guide. Even earlier in 1885, Dr. August Weismann discussed stem cells using the term “germ plasm” and in 1868 seems to be one of the earliest ever mentions of stem cells in science by Ernst Haeckel, who had a model including “stammzelle’, which means “stem cell” in German.

So the reality is that scientists have been thinking about stem cells for at least almost 150 years.

I was curious what the first ever mention of “stem cells” or “stem cell” was in the media. I’m not sure, but I did check it out in the NY Times. When did this great paper first mention these great cells?

The September 19, 1948 edition contained the first ever mention of “stem cell” in the NY Times that I could find. Nuclear tests on Bikini Island (aka Bikini Atoll) had been going on for some time and scientists in the military were studying the effects on animals including goats. They noted that the “stem cell” component of bone was unusually resistant to radiation:

The white cells were extremely susceptible, but the recticulum, or “stem cell” of the bone marrow, was ray resistant.

Ray in this case refers to “atomic rays” or radiation. Recticulum appears to be an alternative spelling of reticulum.

NY Times stem cells

The April 21, 1949 edition is the first mention of “stem cells” in the NY Times. The topic of the piece is similar to that of the 1948 article, but contains more on stem cells. The piece is entitled “Some blood cells resist radiation” with subtitle “Finding Spurs Recovery Hope for Atomic Victims, Bikini Expert Reports in Detroit”. Now we are talking about regenerative or cellular medicine way back 65 years ago. It was reported that radiation exposure victims whose stem cells had survived had the best chance to survive overall.

For you history buffs, just to show how long ago this was, the all-knowing Wikipedia says that the bikini swimsuit was “invented” or at least given that name around 1946, just a few years before these articles. Thus, readers of the NY Times piece in 1949 that alludes to a “Bikini Expert” would likely have not thought of a bathing suit. Although now, if you can believe it, there is an electric stem cell bra (see “Stranger than fiction: the electric stem cell bra for breast enlargement“.

The history of stem cells is far more complicated than I ever imagined until a few years ago. Keep in mind that stem cell history is being made today too with new discoveries.

CIRM 2.0 Should Include Bridges Training Program

CIRM 2.0The California Stem Cell Agency CIRM seems to be in budget cutting mode these days, which from a general perspective makes sense as CIRM seeks to continue operating on its remaining funding through a longer period of time as far out as to 2020.

However, not all cuts are necessarily positive. For example, CIRM reportedly (note: many within the California stem cell community overall are concerned about this possibility) might be considering ending its fantastically successful Bridges training program. That would be very counterproductive. In fact, the Bridges program absolutely should be a key part of CIRM 2.0.

The Bridges program has successfully trained and continues to train students in 11 California state and community colleges. Such training of young scientists who are passionate about stem cell research should always be a part of CIRM.

California Stem Cell Report quoted Susan Baxter, Executive Director of the CSU biotech program, that if the Bridges program is not continued that:

“(CIRM) will lose significant momentum in its efforts to build and inspire a professional stem-cell-related workforce in California.”

Sure, the focus of CIRM 2.0 has shifted to have a more clinical and translational emphasis, but giving up on the mission of training young scientists would be a step backwards.

As a faculty member at UC Davis, I have seen first hand just how powerful the Bridges program has been and continues to be. I have trained and continue to train Bridges students. I have been incredibly impressed with their intellect, energy, and the sheer overall amount they have to contribute to stem cell research in California. The sky is the limit with these young scientists. The CIRM Bridges program empowers them.

Baxter wrapped up a statement to the CIRM Board on his topic this way:

We urge CIRM leadership in the room today to consider extending and continuing the Bridges to Stem Cell Research program. We welcome the opportunity to discuss the impacts of this program with you further. There is no better investment you can make for the State of California.

I couldn’t agree more.

I too ask the CIRM leadership to continue the Bridges program, keeping an eye toward the future of stem cell research.

Even I as a researcher would say that advancing stem cells to new treatments and cures is not all about research. It’s also about people. You need trained, energetic people to make stem cell treatments a reality.

Behind the scenes at Clinicaltrials.gov with Director Deborah Zarin

Deborah ZarinThis post is the first in a series about the Clinicaltrials.gov website.

This piece is an interview the Director, Dr. Deborah Zarin. I want to thank her for taking the time to answer my questions.

Later, I will post Part 2 in which I discuss my concerns about the trend of for-profit stem cell clinic trials being listed on Clinicaltrials.gov that in my view are not conventional trials.

First a little background on Clinicaltrials.gov before I get into the interview.

It is the global clinical trials website with tons of info for anyone interested in clinical trials ranging from patients to doctors to researchers and the list goes on and on. The bonus is its simple, yet powerful search tool, which works go find the specific info that you need.

clinicaltrials.govIn the crazy, exciting, disturbing world of clinical investigative and innovative drug development, Clinicaltrials.gov stands out as a way to learn and make sense of this dizzying arena.

The NIH and NLM maintain clinicaltrials.gov as a website on which clinical trial information can be deposited and accessed by principal investigators of the trials, patients, researchers, and others. It’s amazing.

Here’s the interview with some intriguing insights and information from Dr. Zarin.

1. What is the purpose and mission and Clinicaltrials.gov?

ClinicalTrials.gov provides the public with comprehensive information about nearly 175,000 registered interventional and observational clinical research studies – conducted in the US and worldwide. Of these, summary results are posted for nearly 14,400 records, many of which have not been published elsewhere. ClinicalTrials.gov is the largest publicly accessible registry and results database globally and receives over 112 million page views per month and 57,000 unique visitors daily. (See Trends, Charts, and Maps at http://clinicaltrials.gov/ct2/resources/trends.) Data are submitted to ClinicalTrials.gov through a Web-based Protocol Registration and Results System (PRS) by sponsors and investigators.

ClinicalTrials.gov was established by the National Library of Medicine (NLM) in 2000 in response to the Food and Drug Administration Modernization Act of 1997 and to support NLM’s mission of disseminating biomedical knowledge and advancing public health. Since that time, ClinicalTrials.gov has expanded significantly to support other international registration policies such as the International Committee of Medical Journal Editors (ICMJE) policy requiring prospective trial registration as a condition of publication. Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 801) expanded mandatory registration requirements under previous Federal law to include non-phase 1 trials of FDA-regulated drugs, biologics, and devices, and additional information describing each study. FDAAA 801 also established a results database. (See History, Policies, and Laws at http://clinicaltrials.gov/ct2/about-site/history and FDAAA 801 Requirements at http://clinicaltrials.gov/ct2/manage-recs/fdaaa.)

The continued growth in the use of ClinicalTrials.gov can be attributed to U.S. Federal law as well as international recognition of the scientific and ethical importance of registration and results reporting. The combined registry and results database provides access to critical information about ongoing and completed clinical research for patients, healthcare providers, and policy decision makers. For example, potential study participants, clinicians, and researchers can identify trials of interest, examine summary protocol and recruitment information for ongoing trials and summary results information for completed trials. Journal editors, peer-reviewers, and readers could use ClinicalTrials.gov to examine the prespecified outcome measures and look at the summary protocol information for changes not described in submitted manuscripts and publications. Systematic reviewers could search for unpublished trials and results. An unanticipated outcome has been the use of ClinicalTrials.gov data to provide a window into the “clinical research enterprise.”

2. Are there certain trials that must be submitted by the PIs to Clinicaltrials.gov?

In the United States, two of the most relevant requirements are FDAAA 801 and International Committee of Medical Journal Editors (ICMJE) trial registration policy. FDAAA 801, a US Federal law, includes a legal mandate for a study sponsor (or its designated PI) to register and report results for certain non-phase 1 interventional studies of FDA-regulated drugs or devices. There are substantial penalties for non-compliance. Rulemaking for this law is currently in process, though the provisions took effect starting in 2007. The ICMJE policy requires trial registration of any interventional study, regardless of phase or intervention type; penalty for non-compliance is that a journal will not consider the manuscript for publication. Other key international registration laws and policies are listed at http://clinicaltrials.gov/ct2/manage-recs/background#WhyRegister.

3. Are there certain trials that would be prohibited from being listed on Clinicaltrials.gov? If so, for what reason?

ClinicalTrials.gov accepts information from study sponsors or investigators, anywhere in the world. The only requirements are that a biomedical or health-related study (1) involves human subjects and (2) complies with prevailing laws and regulations (e.g., ethics review).

3b. Follow up. Can you please tell us more about the legal, regulatory, and ethics reviews?

We specifically ask for IRB info (menu of options includes: pending, approved, exempt)—and don’t allow studies to go into “recruiting” or “open” status until they have stated that they have IRB approval. We ask for, but don’t systematically enforce, a copy of at least one IRB letter.  We don’t investigate other aspects of regulatory or legal status—it’s just something that the responsible party has to “certify” to us.  We list the oversight authority as a service so that if there is an alleged problem the public (or we) know what entity might have oversight. This is especially true for non-US studies, for which we might not know anything about the regulatory system.

4. What investigators submit a trial for potential inclusion in Clinicaltrials.gov, how does the Clinicaltrials.gov team determine whether to allow the trial on the website? What kind of vetting is done? Is there an honor system component?

ClinicalTrials.gov contains clinical study information submitted by nearly 12,500 study sponsors including the U.S. Federal government, pharmaceutical and device companies, academic, and international organizations.

ClinicalTrials.gov establishes one Web-based PRS account for each organization (such as a company, university, or medical center) after an application is submitted and reviewed by a staff member. All investigators from that organization who are conducting studies are typically designated as users in this single PRS account. The organization generally designates one or more PRS administrators to manage the account and create logins for additional users.

Each submission goes through a two-step process: (1) automated validation rules to detect missing information for required data elements and clearly invalid data (e.g., characters when numeric data are required) and (2) a manual review process focuses on apparent validity, meaningful entries, logic and internal consistency, and formatting. We do not assess the external validity of submitted information because we do not have a validated “reference standard” against which to check.

5. Does Clinicaltrials.gov have a specific policy about for-profit trials? If there is no formal policy, can you speak to your perspectives on this issue?

No, ClinicalTrials.gov does not have any formal policies regarding for-profit trials. We encourage (universal) registration and results reporting for all clinical studies that comply with prevailing laws and regulations, regardless of funding source and other characteristics. As mentioned previously, we strongly believe that transparency is important for all biomedical or health-related research studies involving humans for both ethical and scientific reasons. (See Why Should I Register and Submit Results? at http://clinicaltrials.gov/ct2/manage-recs/background.)

Our perspective is that, as with any scientific endeavor, clinical research exists in the context of a larger “ecosystem” involving many key stakeholders, including researchers, participants, funders, investigators, regulators, and systematic reviewers. As such, the potential scientific and ethical contributions of a particular study (and design) should be considered within the context of the overall environment. For example, what is already known about the question being studied? What related studies have been conducted and what were their findings? What relevant studies are currently underway?

We see ClinicalTrias.gov as a tool to help people answer such questions before a study is initiated. Once a study is planned, we believe that it needs to be registered and, after complete, summary results need to be reported in order to inform the clinical research enterprise and advance evidence-based medicine.

6. As we discussed, I am concerned about certain trials that are listed on Clinicaltrials.gov because in my view they may be more about generating profit and less about helping patients or generating data. In a general sense is it possible that Clinicaltrials.gov might in the future conduct more vetting of submitted trials? If stakeholders are concerned about certain trials is there a mechanism whereby they can express their concerns to the Clinicaltrials.gov team?

ClinicalTrials.gov is not able to assess the quality of clinical research studies – that is the role of funders, regulators, and ethics review boards, among others. The role of ClinicalTrials.gov is to make information about clinical studies publicly available, allowing others to analyze these data. This includes the ability for stakeholders knowledgeable about particular domains to assess the quality of trials for which information is posted on ClinicalTrials.gov. [Analogy: PubMed provides the public with access to bibliographic information about biomedical articles published in peer-reviewed biomedical journals. Publishers, journal editors, and peer reviewers are responsible for vetting the manuscript before publication. Other researchers can critique published articles, further advancing science.]

In general, we ask stakeholders who detect actual errors in a record posted on ClinicalTrials.gov to contact the organization or person who submitted the information (e.g., Sponsor). For legal concerns, stakeholders should contact the regulatory agency or oversight body that has jurisdiction over that trial.

7. Clinicaltrials.gov does not currently list on the website all the information that it obtains about trials such as the specific IRB conducting oversight. Might there be a mechanism in the future whereby concerned stakeholders could make suggestions about policies related to the website such as including more info like IRB providers, costs that patients have to pay to participate, and such?

HHS will soon be issuing a Notice of Proposed Rulemaking (NPRM) regarding the FDAAA requirements for ClinicalTrials.gov reporting. Once published, the public will have 90 days in which to comment. Many of these issues will be covered (e.g., what information must be submitted, and what information will be made public.)

To be notified about the publication of the NPRM, please subscribe to our FDAAA-UPDATE-L listserv at https://list.nih.gov/cgi-bin/wa.exe?SUBED1=fdaaa-update-l&A=1.

8. What is your vision for the future for Clinicaltrials.gov?

We envision continuing our ongoing, iterative process of making incremental improvements to the ClinicalTrials.gov site. For instance, maintenance of our structured data elements is needed to ensure that new study designs can be represented accurately and searched as the scientific fields evolve. Another important area is keeping abreast of new issues that are of interest to our users so that our records and search engine can be modified, as needed, to support their needs (e.g., patient registries, CER). Ongoing examination of how we categorize stem cell studies, and whether or not we should be requiring the submission of information about whether or not payment is involved, are other examples.

ClinicalTrials.gov provides key stakeholders with a tool that they can use to ensure trial transparency and to monitor and evaluate issues of trial methodology. The ultimate value of this tool will depend on how people use it. This is influenced to a large degree by laws, policies, and the overall incentive structures that influence clinical research. Some of the biggest changes, therefore, are likely to come in the form of new and modified policies that will influence how people use the ClincialTrials.gov system.