Rejuvenating gonads with stem cells

January 12, 2011Carole 28 Comments »

Harvard scientist Jon Tilly proposed a radical new idea about how eggs are produced that called for the existence of ovarian stem cells which could continually produce new eggs. Stem cells are accepted as essential to sperm production in males. In men, the sperm stem cells (called spermatogonia)  produce daughter cells that either make the final end product (new sperm cells) or make more stem cells in a continuing cycle of renewal.

Although accepted as dogma in the male system, the dogma regarding the ovary denied the existence of a renewable stem cell that could continually produce new eggs. The existing dogma was that every baby girl is born with all the eggs she will ever have and her eggs continually die off with age and are lost monthly after puberty. The ovarian stem cells was believed to only produce a defined number of eggs for a short time during fetal development but then became dormant for the rest of the female’s lifespan.

The problem with this dogma was that Tilly’s accounting of eggs lost in his experimental systems always ended up with more eggs than expected. The only way he could reconcile this discrepancy was to allow for the existence of a small population of ovarian stem cells which were capable of reactivating and contributing some eggs to the total. Most of his science colleagues were sure that he was wrong. It took him four years to prove the existence of these reactivated stem cells in the ovary by showing that stem cells he recovered from an aging ovary could be induced to make eggs again.

Tilly used cells from aged mouse ovaries, exposing them to the cellular environment of younger mouse ovaries and ‘reactivating” or rejuvenating the old stem cells which then started to produce eggs again. If the same could be done in humans, old ovaries could be reawakened to produce eggs. This would be a huge advance in the treatment of infertility since ovarian aging is considered irreversible. The only current treatment option for old ovaries which no longer produce eggs is to do IVF using eggs from a younger donor.

Unfortunately, it will likely be years, if not decades, before these scientific findings in a mouse model are converted to clinical treatments for patients. The typical path for moving a scientific discovery from bench to bedside treatment is excruciatingly slow because the clinical treatment must be proven to be both effective and safe. For reproductive treatments which produce children, the safety and health of those children is the primary concern.

First, treatments must be shown to be safe for both mother and offspring in other animal models, especially other primates like rhesus monkeys and chimpanzees. In vitro experiments with rare donated human ovarian tissue would  also be necessary.  If all the animal research and in vitro human tissue work still looks promising, clinical trials might start in humans, if institutional review boards give approval for the proposed research in humans. Because in vitro fertilization research is not funded by NIH, and stem cell funding is subject to erratic funded by NIH or individual states, this research will be slower to yield new clinical treatments compared to  other non-controversial areas like cancer research.

Although anyone reading this today is unlikely to benefit personally from this research, it still opens a small door to the possibility of new treatments for advanced maternal age that don’t involve giving up the genetic link between mother and child.

You can read more about Tilly’s research in this BioTechniques article “Where do babies come from?”.

Another scientist, Karim Nayernia, professor of stem cell biology at Newcastle University’s Institute of Human Genetics, is researching the use of spermatogonial stem cells to revive fertility in the male, after chemotherapy or disease. In mouse studies, he was able to use stem cells from bone marrow and coax it to become sperm stem cells called spermatogonia. Transplants of these new stem cells into mice whose testicles were depleted of stem cells allowed the mice to father offspring. In 2009, his research team reported that they successfully produced human sperm-like cells from embryonic stem cells in vitro. There remain questions about the health of the mice offspring so this research is a long way from clinical use, but offers the possibility of new treatments for male infertility.

Another researcher, Richard Behringer, professor of genetics at the University of Texas MD Anderson Cancer Center has been using stem cells to understand what makes us male or female. His research may one day allow same sex couples to have genetic children together. First, he took stem cells from male mice, cultured them in such a way to cause the X and Y chromosomes to separate in culture, creating some daughter cells that were XO, a genetic type that creates a female genotype due to lack of a Y chromosome. Genetic material from these XO cells was used to replace the genetic material inside a mouse blastocyst. A surrogate mother mouse carried the XO blastocyst and gave birth to a female pup. The ovary of the pup produced eggs that contained DNA from the feminized male stem cell. This female offspring  mated naturally with male mice to produce offspring from (essentially)  two males.

Dr. Behringer is also investigating techniques to introduce a second X chromosome into an XO cell, creating a female egg cell from a male stem cell. There are decades of basic biology research to be done here which will provide insights into how sex differentiation works. These preliminary experiments are decades away from clinical use and may never be implemented if society as a whole remains uncomfortable with using science to circumvent male-female procreation.

Reproductive research has always been controversial. IVF was considered amoral and possibly dangerous in the beginning and yet is widely accepted today.  Public opinion tends to come around if a new medical intervention is effective and causes no harm. If nothing else, stem cell research is unlocking the most basic secrets nature has and although we can’t predict what new fertility treatments, if any, might arise, it is certainly worth understanding reproduction at the cellular and  molecular level. Stem cells are proving extremely useful for reproductive research.

© 2011, Carole. All rights reserved.

28 Responses to this entry

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  • charia2626 Says:

    You may be wrong! The procedure might be available SOONER than you think. I am going for a procedure next month for fertility. So don’t say that anyone reading this won’t benefit. I will post on the internet if my fertility comes back. I am in my 40’s and am anxious to see if Tilly is right.

  • Carole Says:

    I hope that I am wrong. Best wishes to you!! For your safety, make sure that you are enrolled in a clinical study that has been evaluated and approved by an Institutional Review Board for human subject safety.

  • Laura Says:

    Hope you are wrong, too.

    FYI – human trials using mesenchymal stem cells is slated to start in October 2011 for the treatment of premature ovarian failure.

  • Betty Says:

    Hi Laura,

    Can you tell me who/which institution will conduct those human trials in October? I would be interested to know more specifics. I would love to believe that Carole is not correct but I tend to believe that she is. Thank you.

  • Lee Says:

    Hi Laura:

    I would like to participate in the human trial. Is it possible for you send. Me information? It would be greatly appreciated, thank you, lee

  • Sandra Says:

    I will like to participate in the trial as well. I’m 42 yrs old, have 3 kids. Got rmarried with tubes tied. Had failed Ivf’s. I miscarriage with Ivf. Please keep me informed.

  • charia2626 Says:

    I’m not waiting for any trial. That’s too too far away. I already did my procedure…. I just need to wait to see if it works. Any of you who are over 40 have no hope in biological kids unless you do something to make new eggs. I never found out what Carol said that she and everyone else wishes she is wrong. I hear and read about so many desperate older women wanting a biological child and I want to scream to them there is a miracle. It’s too soon to tell but keep up the prayers.

  • thoughts Says:

    It’s not just fertility at stake here — but also women’s overall health. If we could restore ovarian function in women with ovarian failure, they would have better long-term health and happiness. I really hope there’s a cure in our lifetime. There’s so much focus on creating a child, but our ovaries help us with everything from sexual desire, to cardivascular health, to bone health. Restoring normal ovarian function to those who have lost it due to chemo or other idiopathic causes would be a god send.

  • Carole Says:

    Thanks for your comment. You are quite right; functioning ovaries provide many benefits to us that are lost with aging. Because the stakes are so high; I feel it is even more important to approach research trials with caution. Not all stem cell interventions are performed under the supervision of a human research review board. The purpose of an institutional review board is to make research trials- where outcomes and side effects are usually not completely known- as safe as possible for the people who participate. We all want cures yesterday but we can’t afford to willfully ignore real risks that exist when we agree to medical interventions that are not yet-and may never be- the standard of care.

  • Laura Says:

    I’m leaving in January for treatment and of course ethical checkpoints have been made for this trial. We have also spoken to a stem cell researcher at a top Canadian facility and he has suggested questions to ask. I believe since it is a part of scientific exploration, rather than stem cell tourism, I am more comfortable participating. I’ll ask for the doctor’s permission to post his name and hopefully I’ll have some positive news to report to you. You’ll probably have to look to other countries like we have because doctors here will be slow to accept stem cells as a possible treatment option for POF. They’d rather prescribe synthetic hormones, which do nothing to address the underlying causes and subsequent health issues.

    We have chosen this controversial route after repeated failures at the fertility clinic, even with the use of donor eggs. We just don’t believe in the approach used in North America any more. Success is definitely the exception rather than the norm at fertility clinics and we all need to question who benefits from the money that is spent there. So before our decision is judged, please consider what we have been through – especially if you are a medical doctor. This potential treatment, if realized, is an exciting GAMECHANGER for those of us with POF who have been abandoned by our fertility doctors.

  • Carole Says:

    I agree it would be a game changer if the potential of stem cell therapy was realized. But every time the stakes are so high and patients (or anyone) wants something so badly, they become a vulnerable population and need to be protected. That is the necessary role of institutional review boards who oversee proposed human experimentation and work to limit the potential harm to patients. I am sorry you felt abandoned by your doctors, but unproven protocols can be dangerous and sometimes the best way to care for a patient and do no harm to them is to say, No.
    I do think stem cell research has great potential to do good but stem cells are not fully understood and are not entirely benign in every setting. For instance, stem cells can reproduce themselves as effectively as cancer cells. This attribute may explain the origin of some cancers and yet stem cells may be useful in treating some cancers. Confusing? Yes, absolutely. Stem cell biology is complex and as a research area, is in its infancy and any stem cell therapy is likewise in the most preliminary stage. http://stemcells.nih.gov/info/2006report/2006chapter9.htm This NIH site has a lot of info about stem cells and stem cell therapy. Be informed.

  • Beverly Jones Says:

    This treatment to me sounds like a miracle, having suffered with POF, I am now 45 so wonder if I am too old to benefit from Stem Cell Therapy. I would definitely want to make sure it was properly tested for Cancer causing properties.

  • charia Says:

    As for anyone following my treatment. Peripheral stem cell (NOT germ cell) injections have NOT worked. I am not the only one who did this. It simply has not worked. I am experiencing perimenopause. I am happy I did the fetal stem cell transplant in the Ukraine and do recommend it but NOT for fertility. Do not despair. Scientists are working on using iPS cells for eggs AND doing germ cell injections into the ovaries. This should be here hopefully soon. I am following studies from Germany and Israel and will continue my search. I hope it will be here asap!!! Just do not despair. They are working on it!!!!!

  • Carole Says:

    I second the cautionary note. 60 Minutes did a expose on scam artists who were selling fraudulent stem cell cures. http://www.cbsnews.com/video/watch/?id=7394380n Clinicaltrials.gov (http://clinicaltrials.gov/) has a listing of clinical trials that are supported by NIH or private support- and are legit. The FAQs page has explanations of what a clinical trial is and isn’t. http://www.nlm.nih.gov/services/faqctgov.html As much as we all want to find cures—and stem cells have amazing potential—anyone that claims they have a proven miracle cure for post-menopausal ovaries available for routine clinical treatment TODAY is lying. Be careful.

  • MARY Says:

    I’m interested in ongoing trials with stem cells in ovaries for fertility issues (for perimenopausal women), I’d like to participate
    I don’t know if there is any centre in Europe or not
    thank you

  • Carole Says:

    Mary,
    I am unaware of any clinical trials in Europe. Although there have been very promising research studies in mice suggesting stem cell therapy may be effective http://www.biomedcentral.com/1743-1050/content/3/1/6 there aren’t a lot of clinical trials currently. Most of the clinical evidence we have for the possibility of stem cell rejuvenation (sort of) are from studies with cancer patients who have recovered some ovarian function after transplant back of their own tissue (or from a genetically identical twin) http://blog.oncofertility.northwestern.edu/2012/03/ovarian-tissue-induces-puberty-after-stem-cell-transplantation/ Actual reactivation of possible stem cells in ovarian tissue of women who have or are undergoing menopause is still basic research for the most part. Professor Tilly, author of the Nature study that demonstrated ovarian stem cells in mice has established a private company OvaScience which is working on bringing some clinical applications to patients in a few years after clinical trials are complete http://www.fertilethoughts.com/forums/high-fsh-premature-ovarian-failure/713944-oocyte-stem-cells-study-confirms-potential-treatment-infertility.html The company is working on a method to transplant mitochondria, not stem cells, to rejuvenate eggs at the time of ICSI. This is an older idea that has been around for over a decade. More on OvaScience here http://ovascience.com/technology/ Best Wishes, Carole
    http://blog.oncofertility.northwestern.edu/2012/02/do-adult-women-have-ovarian-stem-cells/

  • Can ovarian stem cell technology replenish ovarian reserve? | Fertility Lab Insider Says:

    […] to continually replenish this “starter” population of cells.  In a previous blog post, Rejuvenating gonads with stem cells, I discussed Jonathon Tilly’s landmark studies which showed that mouse ovarian stem cells […]

  • Kim Says:

    Dear Laura,

    Where and who did you talk to in Canada in regards to Stem Cell research?
    Where did you go for treatment and did it work out?
    PLEASE RESPOND SOON

  • Kim Says:

    Does anyone know where Laura went to for the Clinical trial for stem cells and who she talked to?

    Please respond, I would like to try the experiment.

  • Skye Says:

    Hi, I’m very interested in getting in touch with the women in this thread who are looking for experimental procedures. I’m looking too, and it’s daunting!
    thanks,
    Skye

  • Carole Says:

    Hi Skye,
    I have sent an email to Ovascience (http://www.ovascience.com/) to see if they have any clinical trials that are open to enrollment. If they respond, I will post their response. Good Luck!! Carole

  • Tullete Says:

    Where and whom do I contact to get my ovaries rejuvenated.Please respond.Thank you

  • christian Says:

    If anyone can PLEASE tell me where there is a trial. I am even looking (was already planning to go abroad) abroad for stem cell treatment. PLEASE if anyone knows more about any place ANYWHERE in gods green earth please let me know and Ill take the first plane out. I am 44 (just turned) and NO KIDS b/c I took my fertility for granted. HELP!

  • Carole Says:

    Christian,
    Here are a list (numbers 1-4) of a handful of trials -some overseas- on the US government website, clinicaltrials,gov. You will see that some are still recruiting patients but not all are for therapy, some are for basic research. Click on the link to learn more. http://clinicaltrials.gov/ct2/results?term=ovarian+stem+cells&Search=Search This US company is developing human clincal therapies- http://www.ovascience.com/about/ You can contact them and see if they are recruiting or providing the therapies. Good Luck! Carole

  • Gaz Says:

    I hope this stem cell ovary rejuvenation therapy is available to women sooner than later, not decades away as this article describes.

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