Poll for #ISSCR2016 attendees: what’s your view of REGROW Act?

Shinya Yamanaka at #ISSCR2016 on reprogramming of cells & scientists

The second day of ISSCR 2016 started off with a great session on pluripotency and plasticity, and the first talk was by Shinya Yamanaka. He changed the title of his talk to “Reprogramming of Cells and Scientist”. As with my other posts on this meeting, this one is a stream of quotes and impressions from the talk. The beginning was more autobiographical on his part and then the second half was on basic science. I really enjoyed this talk overall.

It’s now been a decade since Shinya Yamanaka’s seminal paper on mouse IPS cells. Shinya started his talk going back in time to the early 1990s of his postdoc at the Gladstone. He cloned NAT1 as a postdoc (Yamanaka et al. Genes & Dev, 1997).

Shinya Yamanaka

He found that NAT1 is required for early mouse development. He made NAT1 null mESCs and found that the NAT1 KO mESCs could not differentiate.

He got his own lab in 2000 and he and his group tried to induce pluripotency in somatic cells. It was 6 years later that they published the first IPS cell paper.

IPS cell technology has “reprogrammed me too” he said. One of the things I enjoy most about Shinya’s talks over the years (besides the wonderful science) is that he is very free with discussing what it means to be a scientist and how science effects scientists including on a personal level.

He noted that after human IPS cells, “I have been spending a lot of time in talking with people in government and industry and banks, and also spending a lot of time in fund raising.” I think this is what he meant by reprogramming of him by IPS cells.

“Some portion of myself is refractory to reprogramming. That part tells me I should enjoy basic research” and then he said that’s what my talk will be on: basic science.

He focused on NAT1 and its knockout in mESCs. Could NAT1 KO mESCs be in the ground state even without 2i treatment? NAT1-nulls even without 2i have the same morphology as WT cells in 2i. They did single cell RNA analysis. 2i makes WT mESCs more uniform in gene expression with higher Oct4 levels, etc. NAT1 nulls even without 2i are very similar to 2i WT cells. It seems NAT1 is an inhibitor of the ground state.

What about NAT1 in human ES cells?

Conventional gene targeting in human cells didn’t work. They could only get hets but no homozygous KOs (unpublished work of Kazu Takahashi). So it seems NAT1 is essential to human ES cells. Importantly, Kazu could get homozygous in the context of Dox NAT1 transgene. When you then remove Dox you get basically a complete NAT1 knockout. 2i LIF supports self-renewal of NAT1 null IPS cells. The NAT1 null IPS cell show higher than WT levels of OCT4 and NANOG as well as other pluripotency factors.

What does NAT1 do as a protein?

NAT1 is similar to eiF4G and it is known itself also as eiF4G2. They function in translational control. eiF4G is an essential linker in translational initiation. They searched for NAT1 binding proteins by doing flag tag IP. It binds to many translational proteins and many similar factors as eiF4G. There are a few things that eiF4G binds that NAT1 doesn’t.

Does NAT1 have general or specific translational regulatory functions? There might be some specific ones.

When NAT1 is turned off some specific proteins are elevated including KLF4 and PRDM14, two key TFs that are required for transition from primed to naive state. RNAs of these two are not changed so the change is at the translational level.

I can’t wait to hear more in the future about NAT1’s role in pluripotency.

Thought provoking talk from John Dick at #ISSCR2016 on cancer stem cells

Professor_John_Dick_FRS

Wikipedia photo

Dr. John Dick gave a great talk yesterday on cancer stem cells here at ISSCR 2016. Below I summarize his talk and as always with these meeting blogs, the post is not polished and is more of a stream of the speaker’s main points. He started out broadly with a nice introduction to this area of research.

There’s a lot of controversy around cancer stem cells (CSC). How many tumors have CSCs? How different are cells within the same tumor?

The normal hierarchical organization of hematopoiesis is disrupted in AML. Are CSC properties clinically relevant in leukemia?

Here the focus is on leukemic stem cells (LSC).  If a patient’s cells can engraft a mouse then that patient has much worse survival. This engraftment predicts relapse. They have developed a LSC prognostic score. NMP1mut FLT3-ITD neg cells are mentioned. miRNA signatures and epigenetics matter for survival. Big picture conclusion: stem cell properties are very important to the disease.

More genetic studies. Branching tumor evolution during leukemia development: what is the role of stem cells? They did deep targeted sequencing of the genes known to be important for AML. They discovered a common ancestor gene commonly mutated in AML. (Shlush, Nature 2014). DNMT3a mutation was present in the common ancestor cell. Leukemia blasts can have the DNMT3a and NPM1C alleles, but many only have one marker (suggesting clonal evolution).

This raises many interesting questions.

Where does relapse come from? What is cellular origin? Did the chemo induce changes? Or are there residual cells that then spur a tumor comeback?

There’s no definitive marker for LSC.

Evidence of a long evolution in the preleukemic phase. One model is that relapse originates from rare LSC that evolve before diagnosis and survive therapy.

A fascinating point–cells that preferentially grow in the mouse xenograft are not the predominant one in the patient at presentation but rather the ones that will later kill the patient through relapse. Another model is that relapse stems from a rare CD33+ subset.

Patient gets cancer growing on spine from dubious stem cell treatment

A brief report in the NEJM today highlights the risks facing patients who get stem cell treatment from dubious clinics as one such patient recently developed a large spinal tumor.

Dr. Aaron L. Berkowitz and colleagues describe how this patient who received a mixture of several stem cell types from an overseas clinic was later diagnosed with a very unusual neoplastic growth on his spine.

stem cell tourism tumor

NEJM Figure 1a/b, showing massive spinal tumor (long, brighter region)

The data point to the tumor arising from the stem cell treatment as it was genetically distinct from the patient.

Oddly the cancer defied classification as a particular tumor type. This may in part be due to the fact that he was given a mix of embryonic, fetal neural, and mesenchymal stem cells. It’s unclear which cell type(s) might have led to the tumor. Notably he apparently didn’t get any immunosuppression, which raises the question of his own immune response to the transplants.

This patient received at least three transplants at different locations across the globe outside the U.S. While risks of stem cell offerings are higher in certain countries, there are many stem cell clinics here in the U.S. that sell stem cells without FDA approval and with little if any data to back them up.

The NY Times just published an article on this case and identified the patient as Jim Gass as well as providing more details including the start of the chain of events:

“I began doing research on the internet,” Mr. Gass said. He was particularly struck by the tale of the former football star and professional golfer John Brodie who had a stroke, received stem cell therapy in Russia and returned to playing golf again.

So Mr. Gass contacted a company, Stemedica, that had been involved with the clinic, and learned about a program in Kazakhstan. When Mr. Gass balked at going there, the Russian clinic referred him to a clinic in Mexico. That was the start of his odyssey.”

The impact of sports celebrities getting unapproved stem cell treatments and the press about such situations can be far and wide on the public.

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At #ISSCR2016, $2,000 donation to Summit For Stem Cell patient group

Summit for Stem Cell

Screenshot from Summit for Stem Cell website

Something very unusual and positive just happened at this year’s ISSCR meeting.

Every year in December I give out an award for the Stem Cell Person of the Year to the individual with the strongest positive impact in the stem cell field generated specifically from outside-the-box thinking and actions.

Dr. Jeanne Loring was the recipient in 2015. The award comes with a $2,000 prize that I pay myself. Jeanne declined it, but that money is now going to support an innovative Parkinson’s patient research group called Summit for Stem Cell.

Jeanne and her lab work with Parkinson’s Disease patient advocates together as the overall Summit for Stem Cell team toward the goal of IPS cell-based therapies for Parkinson’s. This is a very exciting area of research. Part of the reason Jeanne got the Stem Cell Person of the Year Award is her unique combination of great translational science and a bigger picture sense of how to make stem cell therapies become a reality.

Putting our heads together regarding the $2,000 prize from last year, Jeanne and I decided along with Summit for Stem Cell leader Jenifer Raub that the money would go to that group to support their outstanding efforts.

Knoepfler Loring Raub

The three of us just met up a few hours ago at ISSCR 2016 for me to give a $2,000 check to Jenifer (see picture above with me, Jeanne, and Jenifer from left to right).

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