Perspectives on Planned Parenthood Fetal Tissue Video

You probably have heard by now about the controversial video (below) showing the senior director of medical services of Planned Parenthood, Deborah Nucatola, discussing the procurement and distribution of fetal tissues from abortions for research.

The film was taken secretly using a hidden camera by anti-abortion activists who concealed their real identities. It was edited for negative impact, raising questions about fairness and context.

Media Matters pointed to three major edits that changed the context in negative ways in terms of perception, making the video in their opinion deceptive. For instance, we do not see in the video the part where Nucatola says, “Nobody should be selling tissue”. The facts seem to be that the Planned Parenthood fees for the tissues are only for the costs involved in the processing and shipment.

One of the firms involved in the fetal tissue distribution is StemExpress of Placerville, CA. You can read more on the controversy and that California connection here in an article in our local paper, the SacBee. Their Editorial Board also published an editorial criticizing the video and bemoaning its politicization.

I agree with that editorial, but they stumbled a bit right at the end by citing the Gordie Howe stem cell case as an example of a reason for why we need fetal research. Dang, I wished they had done a bit more reading on that to realize that case is probably not the best example to cite.Planned Parenthood

The ethical issues involved in the procurement and use of human fetal tissue must be taken very seriously and things such as appropriate maternal consent are crucial. Nonetheless and as much as it is uncomfortable to watch Nucatola somewhat casually chatting about fetal tissue over her lunch, it seems to me that this situation is indeed mostly about advancing a political agenda.

So, regardless of the motives behind the video, was Planned Parenthood “caught” discussing practices that were possibly unethical? Mostly it seems like the answer is, “no”.

However, in the NYT bioethicist Art Caplan was quoted with his concern about one particular practice mentioned in the video by Nucatola: manipulation of the fetus and how the abortion might done in a specific way based on the tissues that are wanted in order to preserve tissues for certain research uses:

“Dr. Caplan said one practice that Dr. Nucatola described in the video was clearly unethical: manipulating the fetus in the womb and using surgical tools in ways meant to preserve certain organs for researchers.

“You cannot, must not, alter how or when you do an abortion simply to obtain tissues you want,” Dr. Caplan said. “Basically, the only concern is the health and safety of the mother.”

Caplan goes on to say he favors an investigation, but by experts rather than politicians:

The allegations against Planned Parenthood should be investigated, he said. But, he added: “I’d like to see it done by independent experts, not by 15 presidential candidates in Congress. It would turn into a presidential-posturing festival.”

While Caplan downplayed the importance of fetal research in another interview on BuzzFeed Science, stem cell expert, Jeanne Loring, was quoted there in the same piece about the usefulness of some fetal research:

“Fetal cells are not a big deal in science anymore,” bioethicist Art Caplan of New York University told BuzzFeed News. “What happened is stem cell tech then came on board, and gene therapy — there’s just other techniques now. ”

Some scientists disagree, pointing out that fetal cells remain useful for medical research. “I understand why people would want tissues like this,” Loring said.

It’s remarkable how little science and medicine know about human development compared to that of mice or fruit flies, and that gap represents a significant problem for human health and medicine. As this video situation evolves we can hope that the politicization remains at a minimum and that the focus sticks to facts. Especially since we are in the middle of a presidential election campaign, however, that hope may be naive.

Stem cell mistaken identity: who are you?

Who_Are_You_album_coverOne of the biggest issues in the world of cellular medicine and also in cellular research is one of mistaken identity.

I’m talking about scientists, doctors, or others thinking that their cells are one type (say type X) when in reality the cells are something else (say type Y).

Or maybe the cells are some mixture of types X and Y.

If you as a scientist talk to your cells (yes, scientists really do this sometimes), you might quote rock group The Who and ask the cells, “Who are you?”

Some cells such as retinal pigmented epithelial cells (RPEs) or beating cardiac myocytes are hard to mistake as anything else because their appearance is so distinctive, but for many cell types things are not so clear. For most cell types, a cell is a cell is a cell at least in terms of how they look. Sure, there can be subtle differences apparent to the trained eye (e.g. I’ve been looking at cells in culture for about 25 years now), but often it is tough to tell when looking at millions of cells by light microscopy no matter who is looking.

In addition, you might have in your culture say 80-90% RPEs, myocytes or neurons (whatever your desired cell type might be), but hidden away in there might be other cell types that both you and (if you are doing clinical work) your patients do not want to be there.

You can do various things to try to maintain purity or get rid of heterogenous cell types such as clonal selection or doing flow sorting, but nothing is going to help deal with common problems such as culture cross-contamination, starting with cells that are heterogeneous to begin with, or differentiating a starting pure population of stem cells, a process that in most cases leads to much cellular diversity. From lab to lab and clinic to clinic, how different lab staff isolate and handle cells in distinct ways also can lead to unexpected cell types showing up.

If you are a cell biologist you might be confident that the cells that you are studying are one type when in fact they could be something else or again a mixture. Mistaken cell identity or contaminated cells are a growing concern.

This also gets at the larger question of how we know (or think we know) the identity of cells.

Appearance under the scope? Staining for markers? FACS for markers? Genomic and/or transcriptomic analysis? Functional behavior?

All of the above?

Cell cultures also change over time so even if you start out with the perfect culture after a week or two they will have changed. An important approach is to not grow your cells for too long or they will acquire mutations and changes in function.

Perhaps one of the other most important things to do is not work with multiple cell types in a tissue culture hood simultaneously. There may be more pressure to do that in a predatory clinical lab focused on profit.  If you are working with stem cells you can also

You could end up spending most of your budget just being sure you have the right and most pure cells without evening getting to the point of studying their functions or using them clinically, whatever your goal may be. There has to be a happy middle ground, which today probably means devoting at least relatively more time and resources to being aware of your cells than you have in the past. Genetic tools may be helpful in that regard.

Cases of mistaken cellular identity are probably more common than we all think and they are really bad for both science and cellular medicine.

Huge Hack at UCLA Health: Millions of Patients’ Personal & Medical Data Compromised

On May 5 UCLA Health System determined that its computer systems had suffered a massive hack.

ucla_healthsystem

The cyber attack compromised the data of millions of UCLA patients according to the University:

“the attacker had accessed parts of the UCLA Health network that contain personal information, like name, address, date of birth, social security number, medical record number, Medicare or health plan ID number, and some medical information (e.g., medical condition, medications, procedures, and test results)”

These appears to be one of the largest health system hacks ever. The attack exposed the personal and medical information of 4.5 million people:

“Our investigation has revealed that the personal information of about 4.5 million individuals, including UCLA Health patients and providers who sought privileges at any UCLA Health hospital, was maintained on the impacted parts of the UCLA Health network. At this time, there is no evidence that the attacker actually accessed or acquired the personal or medical information maintained on the impacted parts of the UCLA Health network, but we cannot conclusively rule out that possibility. Thus, we wanted to make potentially impacted individuals aware of this cyber attack and provide them with information about how to protect themselves.”

As best as is known at this point no other UC schools or medical facilities were attacked. A forensic investigation of the attack is ongoing.

CVS photo also suffered a hack.

At some point will privacy become an anachronism?

Review of new Mitalipov Nature paper: IPSC & SCNT approaches to mitochondrial disease

In a new, thought-provoking paper today in Nature, Shoukhrat Mitalipov and a multi-institutional team report a significant advance toward potential novel ways to treat mitochondrial diseases.

What are these illnesses?Mitalipov IPSC paper

Mitochondrial diseases are rare, but devastating disorders caused by genetic mutations. Today they are largely impossible to treat in meaningful ways other than palliative care. Some of the mutations causing these diseases are in nuclear DNA, while others are in the mitochondrial DNA (mtDNA).

The main current approach to prevention is preimplantation genetic diagnosis (PGD) to select for embryos following IVF that lack or have low levels of the mitochondrial disease-associated mutations. This can often work quite well, but for others it only works poorly and it is not an option at all for some women. Other options include to obtain a donor oocyte or adoption, but some women understandably want to have their child be genetically related to them.

Clearly new approaches to prevention and treatment are needed.

One idea that has been much on the radar of late is so-called three-parent IVF (aka “mitochondrial transfer” even though no mitochondria are transferred). The UK has approved the future use of three-person IVF, but it remains unavailable for now in the US pending continued review by the FDA. Mitalipov is also pursuing three-person IVF approaches including via a collaboration in China, where it appears the technology is permitted for use in humans.

In the new research reported today, Mitalipov again tackles mitochondrial diseases, but from an intriguing, different angle: the use of stem cell-based regenerative medicine.

In this paper, entitled, “Metabolic rescue in pluripotent cells from patients with mtDNA disease”, the team reports that they can reverse mitochondrial disease via reprogramming to produce induced pluripotent stem cells (IPSCs) or via somatic cell nuclear transfer (SCNT; also known as “therapeutic cloning”), a method distinct but with some similarities to that which is also used in three-person IVF. Notably, the team also includes scientists from the lab of Juan Carlos Izpisua Belmonte, who recently published a study on potential gene-correction-based methods to prevent mitochondrial disease through germline interventions.

Both via IPSC formation and through SCNT, the team reported being able to create pluripotent stem cells (PSC) with few-to-none mutant mitochondria detectable. The approach was based on using parental fibroblasts from mitochondrial disease patients. These patients’ cells have simultaneously two different kinds of mitochondrial mutations associated with disease syndromes: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and Leigh Syndrome. Keep in mind that these patients have a mixture of wildtype (WT) and mutant mitochondria in each single, individual cell, a condition called “heteroplasmy”.

Intriguingly, the resulting patient IPSCs (each clonally produced from a single patient fibroblast cell) exhibited segregation of the WT and diseased mitochondria. As a result, what this means is that some of the separate IPSC lines were largely or entirely non-heteroplasmic, while others were entirely mutant. Very cool.

It’s important to point out that in 2013, a team lead by Timothy J. Nelson reported this same kind of mitochondrial segregation phenomenon during IPSC formation in a Stem Cells paper. The Nelson team also suggested in that 2013 paper (FOLMES, et al.) that this approach could be used for cell-based regenerative medicine therapies as well. The new Mitalipov group paper builds substantially on this earlier Nelson finding and extends it to include SCNT.

How is this remarkable type of mitochondrial segregation possible if individual cells each contain thousands or tens of thousands of mitochondria, and in the case of heteroplasmy presumably the WT and mutant mitochondria are all mixed together in the cell cytoplasm in a jumble?

While the precise cellular mechanism remains to be proven, the authors indicate that this heteroplasmic segregation often occurs in the fibroblasts prior to production of IPSC. Apparently as the fibroblasts were proliferating prior to reprogramming they in some cases spontaneously segregated their mutant and WT mitochondria into different daughter cells. The proposed result of this phenomenon is that the fibroblasts cultures in some cases contained just three main subtypes of cells: heteroplasmic, mostly or entirely containing WT mtDNA, and mostly or entirely containing mutant mtDNA. Then after reprogramming, which generates clonal IPSC colonies, this segregation phenomenon was present in the stem cells.

The big, exciting takeaway message from this segregation data is that in principle this approach of making IPSC from patients suffering from mitochondrial disease could be used to produce patient-specific IPSC that contain mostly or entirely WT mitochondria. In turn, those “fixed” IPSC could be used for regenerative medicine therapies in these patients via transplantation.

The paper also reports mitochondrial correction via SCNT where nuclei are transferred into healthy donor oocytes that have had their own nuclei removed. The donor oocytes contain WT mitochondria. The new hybrid oocytes, now hopefully containing few if any residual mutant mitochondria, can then be used to produce nuclear transfer embryonic stem cells (NT-ESC). For both the NT-ESCs and the IPSCs containing no detectable mutant mtDNA, the paper reports the cells exhibit a correction of mitochondrial-disease associated cellular metabolic defects. This functional correction is encouraging from a potential future therapeutic perspective.

A few open questions remain for future studies.

I’m very curious to know if this spontaneous segregation of WT and mutant mitochondria also happens inside of patients with mitochondrial diseases. In other words, do some of their cells become WT and some become entirely mutant? If some adult stem cells already present in patients can be identified and amplified that would represent another potential source of cells for therapies, which wouldn’t require reprogramming.

Also, they show that a few hundred genes in the NT-ESC and IPSC still exhibit altered gene expression compared to controls (this is from transcriptomic analysis and note that they also did mitochondrial transcriptomic analysis; Extended Data Figure 7 shown at top of the post shows those results, comparing the different cell lines). What could be the meaning of these expression changes?

I also would be interested to see more data on the epigenetic effects/phenotypes of the different kinds of cells in this paper. For instance, what are the epigenetic states of the different kinds of IPSC with either mutant or WT mitochondria predominating? How do these compare to the parental fibroblasts and to control cells lacking mitochondrial mutations?

Another issue that arose in the paper points to the challenges with making NT-ESC. One of the two NT-ESC lines produced, NT2, exhibited failed enucleation. This means that although the researchers thought that they had removed the donor oocyte’s own nucleus before transferring in the somatic cell nucleus, they had in fact not successfully done so. So they ended up with an oocyte with two nuclei’s worth of DNA from both the oocyte donor and the somatic cell. As a result, the NT2 line was genetically abnormally as it was tetraploid (having four sets of chromosomes). Such a line could not be used therapeutically. Even so, with proper validation and screening such lines in the future could be avoided and the focus could be on genetically normal cells that are produced.

This all highlights the importance of validation and genomic screening. In that regard, it would have been of interest both for the NT cells and the IPSC to see whole genome sequencing data or at least whole exome sequencing to check for mutations. The authors’ efforts in this area were limited to whole mitochondrial exome sequencing.

There’s also still the question of whether SCNT can realistically remain a therapeutic option when reprogramming to make iPSC so far seems to work just as well and be far simpler.

Overall, this is a notable new paper that takes cutting edge technology and runs with it in some creative ways.

STAP cell scandal update: Vacanti, Obokata (小保方 晴子), & More

stap cellsWho can forget the STAP cell scandal of last year?

Now almost a year and a half after the deeply flawed papers first were published, where do things stand?

As an international collaboration there were both American and Japanese sides to STAP.

In the US, STAP still remains eerily quiet.

In a month or so, the one-year sabbatical of STAP cell paper senior author, Professor Charles Vacanti of Brigham and Women’s Hospital and Harvard Medical School, is scheduled to end.

There has been no public disclosure as to whether (or if) there was or is an institutional investigation into the possible roles of Vacanti and his trainee Koji Kojima in the fiasco that ultimately led to the retraction of two Nature papers.

In contrast, in Japan there have already been many serious repercussions for the STAP cell authors including Haruko Obokata, who was forced out of RIKEN after she couldn’t reproduce STAP. See a full STAP cell timeline here.

Just recently it was announced that Obokata has been forced to repay the publication fees for the Nature papers. Not a big deal in it of itself, but still just another repercussion for her. The same article quoted an Obokata attorney that her physical condition is a concern.

Obokata Vacanti

Vacanti and Obokata

Overall there has been and continues to be this tension between the reaction to STAP in the US and in Japan.

Well beyond Obokata, many other researchers in Japan have been negatively affected by the fallout from STAP. I don’t think it’s an exaggeration to call it a scientific disaster. In the US, there has been pretty much no apparent fallout. Who knows, it may stay that way.

In the mean time the retracted STAP papers have become in a relatively short period extremely highly cited publications (e.g. 160 citations for one on GoogleScholar). A brief look makes clear that not all those citations are referring to the papers as an example of what can go wrong either. Some are referring to the supposed science as if it was real, which is pretty sad.

We also never really did hear any meaningful discussion of STAP from Nature either. They pretty much sidestepped any responsibility. Hopefully they have brought online a more rigorous manuscript evaluation system like the one used by EMBO.

Brigham and Women’s and Harvard face another stem cell hot potato in the controversy related to the work of cardiac stem cell researcher Piero Anversa. In that case the institution(s) did investigate and Anversa has sued them over how the investigation was handled. To my knowledge that situation remains unresolved.

Could this other situation be a factor in how those two linked institutions view STAP? Again, for all we know there never was an investigation of Vacanti’s or Kojima’s potential roles in STAP.

As more time passes, I don’t think necessarily it means that the STAP issue will go away on this side of the world. Without more information on how the STAP story evolved here in the US, it seems to me that the STAP issue overall cannot have full clarity and the lessons from it are incomplete. More facts and transparency on how that project developed are needed still. Will that ever happen? I don’t know.