√ Extraordinary Epidermis Regeneration In Child Via Combo Stem Cell-Gene Therapy

Hirsch et al., Fig. 2a

Epidermis regeneration is an important approach to helping patients with a variety of serious skin problems that can arise due to genetic conditions or injuries such as severe burns.

An exciting new Nature paper reports epidermis regeneration on a strikingly large-scale. The child who is the subject of the study suffers from a sometimes fatal genetic skin disease called junctional epidermolysis bullosa (JEB). In fact, in the particular case described in the new paper, the patient would have likely died without some transformative intervention given the severity of his JEB. Instead, after receiving a large combination transgenic skin graft, today he is doing well and has a largely normal epidermis. This encouraging outcome was reported in the paper by an international team (Italy and Germany) led by Michele De Luca entitled, “Regeneration of the entire human epidermis using transgenic stem cells.” Interestingly, this paper also points toward a central role for stem cells in epidermis regeneration and homeostasis.

The patient has a mutation in gene called LAMB3 that causes JEB so the core idea here was to replace the lost epidermis with new epidermis cells with wild type LAMB3 that would hopefully restore the patient’s healthy skin. The patient was in a dire situation after acutely losing 60% of his epidermis and having an overall 80% loss. The team took a skin biopsy from a remaining relatively healthy area and used it to establish cell cultures, which were then transduced with a Moloney leukemia virus encoding a normal LAMB3 gene. They didn’t replace the mutant gene, but rather added a normal copy into the cells too to try to get some of the normal function back.

Transgenic epidermal sheets expressing the wild type gene were grafted onto the patient and remarkably the patient has had a near complete restoration of his epidermis as a result. This recovery was associated with restoration of largely normal LAMB3 gene expression (see part of Fig. 2a above). This is an exciting,  groundbreaking experiment combining cell and gene therapy for the skin in a way previously more often studied in hematopoietic disorders. The use of various versions of a combo gene and cell therapy could help thousands of other people. To be clear, there are going to be risks to this approach as well and perhaps even some negative outcomes, but especially in severe, likely fatal cases, the potential benefits make taking carefully considered risks justified within properly structured clinical experiments.

The very positive outcome of this patient so far is encouraging and some potential negative outcomes have not manifested up to this point. Such potential risks include cancer from viral integrations into functionally important genomic domains or some kind of toxicity from viral transduction or from enforced expression of LAMB3, but the team reports no such serious outcomes to date. Note that JEB itself is associated with an increased risk of skin cancer so monitoring will be important.

There are some interesting scientific findings in the study as well. This kind of therapy could potentially also have led to a dominate profile of a very limited number of the most successful cellular clones within the regenerating epidermis (in fact, I would have expected this to happen to some extent in certain skin regions), but it sounds like that didn’t happen. Hundreds of clones appear responsible for the new epidermal growth, rather than say just a handful of the most rapidly growing. Notably, on the other side of the coin if epidermal progenitor cells rather than stem cells had been responsible for the epidermal regeneration, based on genomic sequencing there would have likely been many thousands of independent clones in the boy’s regenerated epidermis, but there weren’t so this supports a stem cell-basis of regeneration here.

It’s possible over the coming years and decades that some regions of new epidermis in this patient could exhibit drift toward more limited clonal dominance so that should and likely will be monitored. Keep in mind that skin is very dynamic and turns over roughly monthly so things can and likely will change over time. It is also possible that this patient could have epidermal issues later if the new stem cell pool bearing the wild type gene becomes depleted over time or expression from the transgene fades or turns off. If that is observed, new skin grafts from the patient’s own banked corrected cells could potentially be utilized for subsequent epidermis regeneration.

It remains unclear what if any impact the gene therapy’s viral integration at many genomic loci including some at some genes could mean for the boy’s long-term health, but again results so far are encouraging. Even so, monitoring for potential skin-autonomous or indirect effects of this therapy on other organs will be important.

Overall, my initial take on this “N=1” study is that it was a major success so far that may catalyze other similar approaches to epidermis regeneration that could have big, positive impact for the regenerative medicine field and patients. There is reason for cautious optimism.

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√ Highlights #Fogm18 Day 1: Data From Ancient Dirt, Genomics Dilemmas, Car-T, Crispr

There are many genomics meetings out there these days, but The Future of Genomic Medicine meeting (#FOGM18) at Scripps in La Jolla is one of my favorites. This meeting is uniquely empowering.

The people and the talks combine for a one-of-a-kind experience. The venue doesn’t hurt either at the Scripps Seaside Forum. The evening before the meeting I walked from the hotel to the venue and took a picture from below at sunset. If you look up by the palm trees you can see hang gliders puttering award in the sky, likely from the hang glider port just north up near the Salk.

This is now my 2nd year attending FOGM and each time I’ve greatly enjoyed the talks both inside the auditorium and outside just chatting with people. You can see my top 10 takeaways from last year’s FOGM here. I want to thank organizer Ali Torkamani, who took the lead this year, and Eric Topol for inviting me to come speak again.

FOGM venue Scripps Seaside Forum

Yesterday was Day 1 of FOGM18 and it was fantastic. There was a major emphasis on data (both in big and not so big forms), but also humanizing genomics.

Although it is outside my area of expertise, the talks on the Genetics of Human Origins were one highlight for me so I’ll start there as I think it is a fascinating, unusual area of research.

Grad student Viviane Slon of the Max Planck Institute for Evolutionary Anthropology gave an exciting talk on obtaining useable mammalian including hominin DNA from sediments (a.k.a layers of “dirt”). It turns out, you don’t need to necessarily find actual bones or fragments to get useful ancient DNA. Slon used some clever technical approaches to successfully fish out hominin and other mammalian DNA from the sea of heterogeneous DNA in sediment that can be dominated by microbial DNA. This approach opens the door to getting new knowledge of evolution and genetics of human origins. One of the questions I didn’t get a chance to ask was “What is the half-life of DNA ‘out in the wild’ and what influences that?” She also went over a nice approach that allows researchers to distinguish between the ancient DNA and modern human DNA contaminants. Great talk!

Her talk was followed by one given by Eske Willerslev of Cambridge. He gave a wonderful, sweeping overview of how genomics has taught us about human origins and migrations. He started on the Americas and addressed different hypotheses about where the first peoples originated and how they came to this last area that was settled by hominids. Lots of different ideas here and probably strong feelings. It’s interesting how there are also conflicts and tensions between physical and genomic anthropology. He went through global human migrations with key genomic insights. It was a scholarly, but very approachable talk.

One of the lessons from both these human origins talks is how much we can learn from DNA obtained out in the field and also about how complex human migrations likely were with many streams one way and then back, divergent streams, etc.

Most other FOGM speakers talked about “modern DNA and genomics” if you will, what we can do with it, how we can (and should carefully) interpret huge data sets, and how genomics and our world are changing in tandem.

Eric Topol slide, food blood sugar score chart

Eric Topol got things started with a wonderful overview of where we are and how fast genomics is changing medicine, both for physicians and patients. Genomic data when utilized properly can inform health and medical decisions in impactful ways.

Eric also talked about personal health in the context of both genomics and data collected from monitoring. It was striking to hear about how he had his own blood glucose monitored for 2 weeks, kept a food diary, and was able to map out a literal personalized score sheet for himself of which foods impact his blood glucose in different ways.

As for dairy foods, skim milk and especially non-fat yogurt scored poorly for Eric. Dang, I eat those. Being protein-rich is not enough! You need some fat in there. Amongst grains, granola was surprisingly far better than some other things including ciabatta with avocado, oatmeal, rice cakes, etc. I thought granola would be a problematic food for blood sugar. You can see a screenshot of one of his slides above (included with Eric’s permission). Notably, each of us will respond somewhat different to the foods we eat. Also, it seems that human genetics only plays a partial role in blood sugar (and likely other) responses to certain foods and it is thought that each of our own distinct microbiomes may play a relatively bigger role.

Right before I spoke, we all got to enjoy the talk “Genetic and Epigenetics Approaches to Treat Disease and Aging”

by Juan Carlos Izpisua Belmonte, He went over a whole host of cool projects ongoing in his lab, including quite a few involving reprogramming and epigenetic use of CRISPR, much of it to fight aging. Juan Carlos is a fearless scientist who does some game-changing, risky research. The idea of fighting aging via reprogramming related to IPS cell formation is intriguing, but I do worry about the risk of tumorigenesis.

Our session also included interesting updates on the use of gene editing for making next generation CAR-T cells for cancer therapies. For instance, Yvonne Chen of UCLA talked about cool technology evolving to make CAR-T kinds of cells that essentially have a “two-step authentication”-like process for activation that makes them more specific. After our session wrapped up with a panel discussion, Juan Carlos received the 11th Annual Scripps Translational Science Institute Award from Ali Torkamani. Well-deserved.

Other FOGM speakers emphasized the big (does the word “big” even do the magnitude justice?) extent of the data out there and the continuing explosion of data within which are currently existing. Jill Mesirov, Associate Vice Chancellor for Computational Health Sciences here at UCSD, and Jeffrey Hammerbacher at Icahn School of Medicine Mount Sinai, who also used to be Facebook’s head data guy, gave interesting talks. Mesirov updated us on her work on an area that has been a subject that I also work on: childhood brain tumors. She talked about how genomic data has helped classify medulloblastomas into different subgroups with important implications for treatment options for the kids. Her work on the role of the MYC family in medulloblastoma struck a chord for me as that’s something I have also worked on in the past.

We wrapped up with a big picture talk about genetics and genomics from Bonnie Rochman. I’m going to start reading her new book The Gene Machine on the plane back tonight. She is an exceptional science story-teller and does such an effective job personalizing dilemmas. I enjoyed both the science and the patient stories.

Overall, Day 1 was both fascinating and fun for me as a scientist. I learned a lot.

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