Risks for Healthy PBSC Donors? One Family’s Powerful Experience

By Jane Langille

A few weeks ago, I wrote to Dr. Paul Knoepfler after reading his book Stem Cells: An Insider’s Guide because I was intrigued by his stem cell theory of aging. I wondered if his theory might mean that someone who mobilized and donated hematopoietic cells might be shortening their own lifetime supply. After exchanging emails about my daughter’s experience, he invited me to contribute a guest blog as he felt that the complexity of her experience as a donor and the questions I was raising would be of interest to the stem cell community.

Peripheral blood stem cell (PBSC) donation is a miraculous treatment that provides people with high-risk forms of blood cancers and other immune diseases a last chance for a cure when other treatment options are exhausted.

As of December 2012, the number of hematopoietic stem cell transplants worldwide passed the 1 million mark, a remarkable accomplishment reported in a retrospective study published recently in The Lancet Haematology. Data collected by the Worldwide Network for Bone and Marrow Transplantation showed that across 75 countries, 42% of hematopoietic stem cell transplants (HSCTs) were allogeneic and 58% were autologous.

The preparation for cancer patients prior to receiving a donation is brutal. Their immune system is wiped out with high doses of chemotherapy and/or radiation therapy so their body is ready for an infusion of healthy, donated hematopoietic stem cells that hopefully find their way into niches in the bone marrow where they divide and produce healthy blood cells. The human leucocyte antigen (HLA) match between the donor and recipient must be as close as possible to minimize the risk of rejection.

It’s a remarkable treatment that helps many critically ill people. But what are the short and long-term risks for healthy donors?

Those were the questions I was contemplating in the spring of 2013 when my daughter Katherine, 22 at the time, turned up as a perfect match for an unknown patient in the bone marrow registry. I was worried about her decision to donate from two different perspectives: as her mom; and as a health journalist.

Short-term issues

As her Mom, I was proud that Katherine had a big heart and the courage to donate a gift of life to a complete stranger. According to some reports, only about half of the people who are identified as matches in the bone marrow registry follow through. This was the child who had to be bear-hugged for childhood vaccines, so I was surprised she was volunteering for a procedure that would mean self-injecting a growth factor drug, twice a day for four days, followed by leukapheresis, which requires being tethered to blood filtering equipment with cannula in both arms for hours.

I also wondered how she would manage the stress, given that the donation was squeezed in between grad school interviews, final exams and her thesis presentation in her final year of university. The information provided by Canadian Blood Services’ OneMatch Stem Cell and Marrow Network said that donors would feel tired and achy for 5-7 days and there were possible complications of spleen rupture, but those symptoms would return to normal fairly quickly after donation was completed.

Long-term worry

As a health journalist, I had another worry. I didn’t like that the growth-factor drug she had to inject for four days prior to donation had an unproven safety profile among healthy donors and was an off-label use. The consent forms said, “No long-term safety information is available.”

The FDA approved the drug Neupogen in 1991. The drug contains the active ingredient filgrastim, a granulocyte colony-stimulating factor. The FDA approval and subsequent updates show that Neupogen was approved for autologous use among cancer patients, with no mention of allogeneic use by healthy donors. There is also no mention of healthy donors in the prescribing information.

Neupogen

A 2007 paper in the British Journal of Haematology mentions that since 1997, the US National Marrow Donor Program has maintained an Investigational New Drug application for the manufacture of PBSC products from unrelated donors and that “it is unknown whether filgrastim increases or decreases an individual’s risk of developing cancer” but added, “based on limited long-term data from healthy people…no long-term risks have been found so far.” Not exactly reassuring.

The only prospective trial I could find assessing the safety of filgrastim-mobilized stem cell donation and PBSC leukapheresis among healthy donors is currently underway and will not be completed until January 2022. The description says that filgrastim is “not a licensed indication,” and mentions that data collection began in February 1997.

The decision to donate

So the crux of the decision came down to this: should she risk an unproven drug treatment so that she could give a complete stranger another chance at life?

As a 22-year old adult, it was Katherine’s personal decision to follow through. She self-injected filgrastim twice a day and had the usual symptoms of bone aches, headache, and fatigue. She donated over two days, tethered to the apheresis machine for about 5 hours each day in a room where the other 10 treatment chairs were filled with cancer patients receiving chemotherapy and plasma treatments.

Kat-OneMatch-Donation-2

It was an odd juxtaposition for everyone involved, but the equipment and staff were located there. A second day is not always required, but it turned out that the recipient was apparently 15 kg (33 lbs.) larger than she was and the target collection calculation depends on body weight.

After her donation days, she traveled by train back to her university town three hours away to study for final exams and work on her thesis presentation. Three weeks later, she had an enlarged spleen scare, which prompted a visit to her local hospital ER via ambulance and had to restrict her activity to prevent a ruptured spleen. The donation hospital in Toronto then requested she travel back for a check a couple of weeks later. By then, thankfully, her spleen was back to normal size. She was well enough to do a karate grading a few weeks later and over the last two years, has had no complications.

At the one-year mark, she contacted OneMatch to find out if it would be possible to exchange contact information with the recipient, as the rules allow for that if both donor and recipient agree. She learned that the recipient lives in a country where there is a two-year restriction on information exchange. She doesn’t really want to know the recipient, but someday would like to know how they fared with her gift and if it made a difference.

There’s no question I’m proud she followed through with a donation. Even better — she’s proud. Katherine says, “In any case, I’m happy to know that my gift likely brought hope to the recipient and their family.”

The stem cell theory of aging

Dr. Knoepfler provided some helpful perspective about how a one-time mobilization of stem cells might affect a donor’s long-term health. He said, “In principle, boosting production of stem cells for a PBSC donation could have long-term effects. My feeling in the grand scheme of life is that a short-term, one-time mobilization of PBSC is unlikely to have a lasting effect on an otherwise healthy young person. Given the massive turnover in blood cells (something like a trillion blood cells are replaced per week for each of us), our hematopoietic stem cells have got to be very robust and for the dozens of times in our lives when we get sick enough to mount a major immune response, our stem cells are mobilized repeatedly each time.”

Bottom line

Is it admirable to donate and give someone else a chance at life? Of course! But I wish donors could have more information on how the procedure might affect them in both the short and long term, to understand more about what they are risking in order to help someone else. Here’s hoping that the study currently underway finds minimal risks for donors. In the meantime, it was great to get some perspective and reassurance from a scientist working in the stem cell field.

Jane Langille is a health journalist and mom based near Toronto, ON, Canada.

Are babies from same-sex couples really possible?

Since Shinya Yamanaka reprogrammed first mouse and then human ordinary cells into powerful pluripotent stem cells, termed induced pluripotent stem (iPS) cells, back in 2006-2007 many new research avenues have opened up.

The impossible suddenly seemed a lot more possible with the report of iPS cells (aka IPSC). People started asking many more creative questions, The biomedical sciences now had more potential to make the seemingly impossible become reality.

One question that has come up: could same sex couples have their own biological children?

There’s been a lot of hype on this question in the media in the last week including these headlines and stories:

One article claimed that same sex parents could have their own biological offspring within 2 years. That’s just total baloney. However, in the long run within 1-2 decades this very well could be achieved. The excitement and over-exuberance in some cases with the media over this issue stems from recent work published in Cell from the labs of Drs. Azim Surani and Jacob Hanna on a more efficient way to produce human primordial germ cells (PGCs) via iPS cell-related methods.

Hanna was quoted thusly by Newsweek:

“This is very exciting biology,” says Dr Hanna. “We have succeeded in the first and most important step of the process, where we have reached the progenitor cell state for sperm and egg. We have not yet achieved mature sperm and eggs. So we are now focusing on completing the second half of this process.”

stem cell gametesThere’s no doubt that this is important work in this paper, but it’s a long, complicated road to get from the point A of the state of this research today to point B, where it could actually be used to produce human babies.

Still, what is so different now is that one can see a roadmap how to possibly get to that new reality.

Update: It’s also notable that Katsuhiko Hayashi and Mitinori Saitou have been able to produce living mice from stem cell-derived gametes (image above of method from one of their papers and another relevant paper to read; hat tip to Andrew Childs).

“It is probably a long way off, but it would be a way for people who have had treatment for conditions such as childhood leukaemia, which has left them infertile, to have children of their own,” Robin Lovell-Badge, head of stem-cell biology and developmental genetics at the National Institute for Medical Research, told The Sunday Times.”

I agree with Dr. Lovell-Badge on his view of this. Such technology could not only facilitate same sex couples have their own children (in the sense of genetically related to both parents), but also have a number of medical benefits such as tackling the general problem of infertility and more specifically allowing cancer patients who were treated with chemo to still have their own children later on in life as Dr. Lovell-Badge indicated. There’s great potential here even as we should be careful to note a realistic timeline and the health of children produced this way could be an issue.

IPS cell cloning

An additional cautionary note is needed as well related to cloning.

Unfortunately, there’s a ‘dual use issue’ here. This same kind of technology, if applied by some rogue scientists, could be used to clone human beings as well. This kind of technology could lead to both sperm and egg production from a single individual, which when followed by IVF, could in principle produce a human clone. See diagram above of how this could work with an individual male to be cloned (from Stem Cells: An Insider’s Guide). In theory this cloning method could work just as well with a woman too, but for male offspring somehow a Y chromosome would need to come into play. Even if it wouldn’t be easy to get this cloning to work, it might well work with enough money and effort. There are people out there who really want to clone themselves or others too so the motivation is there.

I’m not trying to freak people out, but this possibility of cloning is very possible in coming decades. It’s probably well past time for reproductive human cloning to be formally banned in the US. We still should allow therapeutic cloning of human ES cell lines. Realistically, given national politics, can we hope that politicians would be able to ban one kind of human cloning (reproductive) and still allow the other (therapeutic) to be legal in the US? I don’t know. Probably not any time soon.

As I said at the beginning of this article, amazing new things are possible that once seemed only in the realm of sci-fi, but with the good will also come some complicated baggage.

New Ways of Thinking About Stem Cells: Book Excerpt

Sometimes you think you know a person and they suddenly surprise you by doing something so different that it is shocking or by taking on a new personality.

Cells can be that way too.

Waddington Knoepfler

In my book on stem cells, Stem Cells: An Insider’s Guide (you can buy it here on Amazon–it’s very affordable–or also here at the publisher’s site for some international buyers) published last year, great scientific illustrator, Taylor Seamount, and I came up with a new adaptation (see image above) of a classic model of Waddington that visually explains how cells might change their personalities.

How would the STAP stem cell process fit into this model?

Cell biologist are increasingly viewing cells including stem cells as far more changeable than in the past. For example, one notion is that stem cells don’t really exist as a stable, concrete type of cell. This theory holds that the reality is rather much more complex and that cells can cycle between different identities and functions. For example, an ordinary cell might become a stem cell when under stress.

Yes, the STAP stem cell concept might fall into this larger model. Of course stem cells can also change into non-stem cells when they differentiate or perhaps when they are transformed into cancer cells.

In our Waddington adaptation, the cells are more potent the higher up on the hill they are. They can roll down the hill into  different channels to end up with different fates such as death by falling into a chasm or differentiation into specific cell types like fat or skin cells. An alternate pathway, not previously included in Waddington models, allows for cells to transform into cancer cells. We’ve also got cells being dragged back up the hill to become iPS cells.

How would STAP fit into this kind of model? Maybe acid rain falling onto the landscape?

These kinds of models are both fun and helpful in promoting creative ways of thinking about cells and stem cells.

Book Excerpt: Top 4 Stem Cell For-Profit Good Citizen Biotechs

The below is an excerpt from my book, Stem Cells: An Insider’s Guide.

I hope you enjoy this excerpt and the book, which I think is a really good deal at under $27 paperback or under $17 for E-book version.

Having our innovation and ethics too

In the stem cell field you can have it both ways. As a company, you can be ethical and help patients. There are many examples of stem cell-related corporations doing “the right thing” when it comes to developing therapies based on growing stem cells in the lab. Below I discuss a few of these companies (Disclosure: I have no financial interests in these companies, which are listed in alphabetical order).

Advanced Cell Technology

As one example, let me mention a company called “Advanced Cell Technology” or ACT. I would argue that, especially in the last half dozen or so years, the company has been a model citizen in the for-profit stem cell field.ACTC

ACT’s most advanced product in the pipeline toward the clinic is an embryonic stem cell-based therapy for macular degeneration, the leading cause of blindness. ACT grows the embryonic stem cells in culture and differentiates them through a complex process into special cells called retinal pigmented epithelial cells (RPEs). Macular degeneration robs people of their sight because their endogenous RPEs die off. Therefore, the principle behind ACT’s therapy is to replace the endogenous RPEs with exogenous ones. So far, ACT has reported no major negative outcomes from its trials of transplants of embryonic stem cell produced-RPE. I am discussing ACT here because it follows FDA rules and works in an ethical manner to protect patients. It publishes its data and engages patients.

Athersys

Athersys is an adult stem cell company developing allogeneic products to treat a number of important human diseases. The company has five clinical trials listed in the government database. AthersysThe target diseases include stroke, heart attack, blood cancers, obesity, and ulcerative colitis. Their top-line product, MultiStem, is described by the company in one of their clinical trial write-ups as follows:

“MultiStem(r) is a new biological product, manufactured from human stem cells obtained from adult bone marrow or other nonembryonic tissue sources. Factors expressed by MultiStem cells are believed to reduce inflammation and regulate immune system function, protect damaged or injured cells and tissue, promote formation of new blood vessels, and augment tissue repair and healing.”

Athersys has a good reputation in the stem cell field for transparency including regularly publishing their data and following FDA regulations.

Mesoblast

Mesoblast is another good citizen in the stem cell field and has an unusually large number of stem cell products in the pipeline. Their work is based on a type of cell that they call the “Mesenchymal Progenitor Cell” or MPC. Interestingly, while typically progenitor cells have less potency than stem cells, as we discussed earlier in this book, Mesoblast’s MPCs are not your ordinary progenitor cells. 

Mesoblast_Ltd

I recently heard a talk by Dr. Paul Simmons of Mesoblast who reported that MPCs are in fact more potent than MSCs, which is an interesting paradox of nomenclature. Mesoblast is conducting FDA-approved clinical trials for a host of human diseases. I found 9 clinical trials listed for Mesoblast including for conditions as variable as spinal disc injury and heart attacks.

NeuralStem

NeuralStem is a fourth good citizen in the stem cell for-profit world. They are a model citizen for the field when it comes to transparency says Alexey, who I trust on this a great deal, publishing data and even publicly releasing their patient consent form, a rarity in the stem cell field. NeuralStem currently has four clinical trials listed in the database: two on depression, one on spinal cord injury, and one on Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s Disease).NeuralStem

The key, positive roles of investors in good-citizen companies

It is important to also highlight the crucial role of investors in making safe, effective, ethical, and compliant stem cell treatments a reality. For-profit stem cell companies including the good citizens of the corporate stem cell world need large amounts of cash to make stem cell-based medicine a reality.

The money comes from investors, who are hoping that some of the exciting stem cell biotech companies become profitable. I know from talking with many of the investors that they are choosing to invest in the stem cell companies not just because they believe that they will be profitable, but also because the stem cell products of those companies will potentially help people suffering from diseases and injuries. I believe that the investors in publicly traded stem cell companies fulfill a key role in accelerating stem cell cures. They tend to be a highly educated, engaged group of people as evidenced by their posts on a website for stem cell investors where I sometimes blog as well.

Investors in privately owned companies can also have positive roles, but I am concerned that in that context the lack of transparency may lead to a more complex, potentially ethically problematic influence.

The main overall challenge in a for-profit setting is to create a business regulatory environment in the stem cell field that enables good actors to succeed.

Book Excerpt: Stem Cells for Alzheimer’s Disease–Are We There yet?

Test for Alzheimer's DiseaseBelow is an excerpt focused on Alzheimer’s Disease from my new book on stem cells. Stem Cells: An Insider’s Guide, which is targeted to a broad audience of people interested in stem cells.

Alzheimer’s Disease (AD) is one of the most devastating illnesses. It destroys the brain, which shrinks over time (see image from Wikipedia at left) as the disease progresses.

The toll of AD is not only measured in hundreds of billions of dollars in health care costs and millions of deaths, but also in personal and family tragedy that comes with the severe loss of memory that accompanies it in loved ones.

Remarkably, scientists and doctors are getting better at predicting who has pre-clinical AD or who will ultimately get AD before patients are even symptomatic.

I have to wonder, though, would I want to know I will get AD if doctors have no treatment for it? I’m not sure.

At this time nobody really knows what causes AD. There are also no known convincing ways to treat or prevent it either. However, a number of avenues provide hope for the future and stem cells are one of the most interesting.

For example, the New York Times published an article about a relatively new clinical trial being conducted on a Columbian family that has a strong genetic predisposition to AD. Scientists are testing a treatment on this family using an antibody-based drug called Crenezumab. The drug is an antibody that has as its target the distinctive plaques that form in the AD brain even before the disease becomes clinically apparent. Many other drugs are being developed as well, but an overriding challenge is that, as mentioned above, we do not truly understand AD in the same way that we understand other diseases. Thus, further research is essential.

Another possible approach to treat AD is through stem cell-based regenerative medicine therapies. There are three key possible approaches to using stem cells to treat AD:

Regrow brain cells via cell therapy. One avenue is to use stem cells to regenerate or regrow diseased parts of the brain. This approach is what people most commonly think of when they conceive of treating AD with stem cells. The problem with this approach is that the architecture of the brain is physically integral to memory so even if we could grow a fresh, young part of the brain to replace one ravaged by AD, there would be no memories there. It would be like wiping the slate clean. In theory perhaps the person could make new memories going forward in life that could be remembered or they could be re-educated, but this is not what most people imagine as a successful treatment for AD.

Heal with immunomodulation. Another approach is to use stem cells such as MSCs not as rebuilding agents, but rather as healers of the existing brain tissue. In this way of thinking, MSC could heal rather than replace neurons for example. MSCs are akin to the natural doctors of the body. They could have anti-inflammatory and other powers that might ameliorate AD.

Drug delivery. A third concept is using stem cells such as MSCs as drug delivery agents. So for example, instead of giving Crenezumab or some other drug systemically, it is possible that stem cells could directly deliver a drug (e.g. one that targets plaques the way that Crenezumab does) within the brain from cell-to-cell far more effectively than a drug given systemically.

Some of these same kinds of approaches might be applicable to other diseases as well. However, all of them might be stymied to some degree by the potentially harsh or even cytotoxic environment of the AD brain, which may kill transplanted cells before they had a chance to do anything positive.

There are eight clinical trials listed in the national database for Alzheimer’s and stem cells.

Some of these same kinds of approaches might be applicable to other diseases as well.

For more info on using stem cells to treat other diseases here are links to posts in my disease focus series below.

Cancer Stem Cells: a new target

Disease Focus Series: Cancer

Disease Focus Series: HIV/AIDS

Disease Focus Series: Spinal Cord Injury

Disease Focus Series: Osteoarthritis research moving forward

Disease Focus Series: Parkinson’s Disease and promising new pre-clinical results from iPS cells

Disease Focus Series: a big week of exciting progress on Alzheimer’s Disease

Disease Focus Series: Huntington’s Disease, a major new finding