Genetically Modified Humans Now Inevitable?

human egg editDiscussion of concerns over heritable human genetic modification has spiked in 2015.

This dialogue is a good thing, but is it in a sense too late?

Are genetically modified (GM) people a foregone conclusion?

Rumors are swirling that upwards of four papers reporting production of GM human embryos are in various stages of review at high-profile journals, sparking a sense of urgency for some kind of steps to deal with this new reality. Could these papers report germline correction of the CTFR mutation in cystic fibrosis or of a BRCA1 mutation? Were these GM human embryos used to make embryonic stem cell lines or are they cryopreserved?

The prime concern now is that GM human embryos could in principle be rather simply turned into GM humans at any one of thousands of IVF clinics around the world with a surrogate mother. That simple technological step of going from GM human embryo to GM human being of course invokes incredibly complicated, thorny legal, bioethical and societal issues.

So stakeholders have been weighing in recently on anticipating how to deal with this evolving situation.

Lanphier, et al. in Nature recently made the case in a piece called “Don’t edit the human germline” that GM human embryos should not be produced. Baltimore, et al. argued in Science for increased dialogue, but stopped short of proposing any kind of moratorium. ISSCR called for a moratorium on attempts at clinical applications of human nuclear germline modification.

My own take on this has been a more practical, specific approach that I call the ABCD plan that draws a bright line between allowable in vitro work (under very specific, mandatory rules, training, transparency, and oversight) and in vivo applications.

As this positive dialogue has proceeded, there is a troubling backstory. The sense I’ve gotten from some of those in the know is that there are researchers already intent upon going ahead to make GM human beings. Some believe it is not a question of if, but rather when and under what circumstances.

Interestingly, while there has been talk that from a legal and regulatory perspective that such an endeavor would “not be allowed” currently, I’m not so sure.

For example, here in the US if a GM baby was made, what could anyone do after the fact? Would the FDA really take some kind of punitive action and wouldn’t it be too little too late anyway? What about in China? I’ve heard people say there are regulations against making GM humans in China, but would they be effective?

If it is not too late to stop the production of GM people at this time, are there things we could be doing now besides increased dialogue to chart a safer path forward? If so, my sense is that time is short.

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.

New biotech Semma Therapeutics joins ViaCyte & Betalogics in stem cell Diabetes arena

Semma Therapeutics

Semma’s technology director Felicia Pagliuca, with CEO Robert Millman. Boston Globe Picture

A new biotech startup, Semma Therapeutics, announced that it seeks to fight diabetes via translating technology from the lab of Doug Melton at Harvard to the clinic.

Another major player in cell therapy-based arena for Diabetes is most likely good news for patients.

Quoted in the Boston Globe, there is a good deal of enthusiasm about the potential of this kind of therapeutic approach:

“This would be a huge breakthrough,” said Dr. George L. King, a Harvard Medical School professor and research director at Joslin Diabetes Center. “It could cure diabetes.”

Semma TherapeuticsSemma will have to compete with ViaCyte and Betalogics, which could prove challenging given, for example, that ViaCyte already has an ongoing FDA-approved clinical trial. Still Semma has raised more than $40 million, which is a good start, and this capital came from some known bio-investment players:

“Sensing a business opportunity at the juncture of stem cells and diabetes, venture firms MPM Capital, Fidelity Biosciences of Cambridge, and Arch Venture Partners of Chicago are teaming with Minneapolis-based medical technology giant Medtronic plc to back Semma in the company’s first round of financing.”

Two of the leaders of Semma are former Melton lab postdoc Felicia Pagliuca, and CEO Robert Millman. Pagliuca was first author on a high-profile Melton lab paper in Cell published just about half a year ago and post-pub reviewed on this blog.

The Semma website has more information.

Why the name Semma?

I’m not sure.

There is a SEMMA acronym in high-tech:

Sample, Explore, Modify, Model, Assess.

It’ll be exciting to see how Semma performs and more broadly how cell therapy-based approaches to Diabetes evolve. I view Semma coming on the scene as a positive.

Lisa Ikemoto Guest Piece on Human Germline Genetic Modification

lisa ikemotoLisa C. Ikemoto, Professor, U.C. Davis School of Law

I have been following the reports about genetic editing technology with concern. The fact that some scientists are calling for moratoria on gene editing of human embryos heartens me. Frankly, I had little confidence that any group of scientists could bring themselves to call for limits on research. The call for a moratorium is as much a game changer as the technology itself. It creates an opportunity for research transparency and open exchange between the scientific community and the lay public. Germline modification raises a wide range of scientific, social and ethical issues that we have only begun to consider. The call for a moratorium puts those issues front and center and, if implemented, gives us valuable time for consideration.

In the meantime, as Paul Knoepfler has pointed out, we need is a practical plan for proceeding. His ABCD plan proposes use of SCROs for approval and oversight of in vitro research. The use of existing oversight mechanisms makes sense, although in practice, both IRB and SCRO review is only as rigorous as local institutional culture allows. SCRO review is a decentralized oversight mechanism through which research standards are subject to variable interpretation. However, as Knoepfler points out, SCROs are already in place.

As a bioethics scholar and teacher, I find the bioethics training appealing, fascinating, and daunting, given the wide range of potential issues. I’m glad to see that Knoepfler has flagged sourcing of human oocytes as one issue. In the fertility context, human oocyctes are procured through a largely unregulated and rapidly expanding market. The process of soliciting young women to provide oocytes for others’ use is often degrading and expresses eugenic ideals. (See my recent blogpost here). Federal guidelines and a few state laws prohibit payment to research donors. But I worry that the notion of free market individualism used to explain treating women as sources of raw materials and exposing healthy young women to the risks of ovarian stimulation and oocyte retrieval is being used in research, as well. Do we really want to superimpose market thinking on human beings, in the name of science?

I would hope that bioethics training would take the concerns of disability rights activists seriously. Genetic modification is a form of genetic selection. We have a long, bad history of mis-using human genetic selection. Genetic selection technology use can, and probably will, expand the list of conditions and traits considered undesirable. As the list expands, so will the therapeutic justification for genetic modification. The most important concern is that as the list expands, acceptance of persons with disabilities will narrow. The Americans with Disabilities Act has effected important legal and social changes for people with disabilities, and the Genetic Information Nondiscrimination Act provides some protection against genetic discrimination. But neither limits the use of genetic selection. While this concern applies most obviously to in vivo research, it starts with in vitro research agendas.

The Scientist’s Garden: Spring Has Sprung

the scientist's gardenIn celebrate the start of Spring yesterday, here are some pics from my garden. I have so little time I kind of neglect it, but sometimes it all turns out anyway.

Above you can see the edge of one of the beds with over-wintered & self-reseeded sweet alyssum in white and purple. Intermixed I have tulips and miniature carnations, with the latter surviving the winter. The climate in Davis, CA can be very mild in the winter and this year that was especially true. I like the combinationof purple and white overall. To the right of the flowers are various veggies that grew over the winter and are now exploding including lettuce, beets, dill, carrots, and cilantro.

more scientists garden

Here you can see all kinds of flowers in a gardening riot mixed with veggies.

Then below is a nice sunrise viewed from the garden. Got to stop working on one’s grant early in the morning and go outside sometimes.garden sunset