How did my top 20 stem cell predictions for 2015 fare?

stem cell crystal ball

Paul’s Stem cell Crystal Ball

Each year around this time I check up on my past year’s predictions for the stem cell field. For 2015 I made 20 predictions.

You can see past top 10 predictions lists for 2013 and 2014. It’s pretty interesting to look back at where the focus was in past years and what my crystal ball yielded for better or worse.

How did I do for 2015?

Below is my scoring of the 20 predictions and it’s a mixed bag. I always tend to err on the side of optimism in predictions overall so that usually gets me in a bit of trouble on certain predictions. Note that I have used my exact wording on the prediction from last year even though in some cases I might now in hindsight have changed it.

  • FDA ‘breakthrough’ on stem cells. FDA grants an investigational stem cell biological drug therapy the breakthrough status designation.
    • Score: Wrong. This is a major disappointment.
  • Adult & pluripotent stem cell advances both impress. More encouraging publications and news on the clinical and translational fronts for both pluripotent and adult stem cell drug development including MSCs.
    • Score: Right. It’s been a great year for many kinds of stem cell research.
  • Doc training in stem cells. More new academic-related training programs for doctors to be true stem cell and regenerative medicine specialists.
    • Score: Mixed. There have been for-profits selling more training, but I don’t consider it very real. Some “real” training programs are possibly in the works.
  • Big pharma’s big interest in stem cells grows further. Big pharma’s interest in stem cells & regenerative medicine continues to grow including at least one major development that might be takeover of a stem cell biotech or something else. There are some small stem cell biotechs that seem ripe as takeover targets.
    • Score: Right. Think Ocata, CDI, and more.
  • RTT spread. At least one more state (and probably more) pass Right To Try (RTT) laws setting up a collision course between state and federal laws on investigational drugs including stem cell products.
    • Score: Right. I believe more states now have RTT than don’t. What does it mean though practically speaking?
  • Pro sports gets a bit more serious about dubious stem cell “treatments”. A pro sport players association or league acknowledges growing and difficult stem cell issues for players.
    • Score: Wrong. Lots of crazy stuff going on in the stem cell sports medicine and doping worlds, but league action isn’t one of them.
  • More high-profile stem cell paper problems. At least one and probably more major stem cell paper problems pop up and could include retractions.
    • Score: Right. I guess this just continues the trend of the last few years. Here are just the retractions, but there are a lot more messes out there.
  • The UK Parliament OKs 3-parent baby tech. The parliament approves 3-parent/mitochondrial transfer technology, but more steps are required before it is practiced in humans.
    • Score: Right.
  • Stem cell clinic chains Cell Surgical Network and Stem.md continue to grow for at least the first half of 2015 and probably beyond. They operationally challenge recent FDA draft guidances on adipose and minimal manipulation.
    • Score: Right.
  • STAP-related news on the American front. We learn something on the US side of the story of the retracted STAP cell Nature papers.
    • Score: Wrong. Is STAP considered over and resolved for Brigham and Women’s/Harvard or are they still slowly investigating?
  • Muddier stem cell waters. More mixing of “legit” stem cell companies and researchers with the non-compliant side of the tracks.
    • Score: Right. This one is really troubling. The legit and dubious are often doing a stem cell dance together now.
  • More stem cell paper debates and developments on PubPeer. A volatile trend continues with notable twists and turns.
  • IPSC RPE safety. The IPSC-based RPE trial for wet AMD in Japan continues in 2015 without a reported safety hitch.
    • Score: Wrong. Although regulatory reasons were indicated as the key factor, when the clinical study stopped, mutations were also mentioned. It’s not clear how important this mutations might be.
  • A stem cell biotech finds itself in a hairy situation. What a tangle.
    • Score: Right. I was right on this even if the company (Ocata) wasn’t the one I thought would be in a mess.
  • At least one patient is harmed or files suit for a dubious stem cell clinic treatment. This is a sad prediction, but unfortunately I think it is likely.
    • Score: Right.  This happened in Japan.
  • VSEL hell. There will be even more bad news for these Sasquatch of stem cells after the Weissman lab paper that seemed to refute these “very small embryonic-like” stem cells in 2013. What does this mean for NeoStem ($NBS)?
    • Score: Mixed. It’s coming but just not yet in the public domain…
  • Celltex is going for an IND. This is an interesting development.
    •  Score: Mixed. Another one where I think it is coming but not yet openly.
  • GOP on stem cells. Republications make some noise on stem cells or personhood.
    • Score: Right. I’m going to score this right given the Planned Parenthood mess on fetal tissues/cells.
  • FDA back in the game of taking action on dubious stem cell clinics. After a long quiet period in 2014, the FDA takes some action on dubious stem cell clinics.
    • Score: Wrong. What can I say? They mystify me.
  • Stem cell-based organs. The red-hot trend of bioengineering organs and tissues in part using stem cells as a material continues to develop.
    • Score: Right. Can you say “organic”?

TGIF science links: CRISPR, stem cells, caffeine, & more

I always like to do a bunch of science reading on the weekend when it’s quiet. Here are some TGIF science links to thought-provoking reading.CRISPR pigs

 

 

 

 

 

CRISPR stuff

Where in the world could the first CRISPR baby be born?

DIY CRISPR on the horizon soon?

CRISPR-y pigs to yield “bacon” of human organ transplants?

Stem Cells

Mini-kidney, nephron organoids from stem cells give hope

Still time to vote for the Stem Cell Person of the Year here.

German-US partnership on IPS cell including Jeanne Loring.

Sleepy stem cells are sad and bad for transplant?

Other interesting reads

DrugMonkey talks bad prof behavior

Want a downer? Check out the RetractionWatch leader board.

Cellebrate Cell Day in November.

Bees high on caffeine do what?

Healthy skepticism needed on claim of stem cell-derived human fetal brain

human fetal brain IPSCOne of the biggest claims related to stem cells and in particular to induced pluripotent stem cells (IPSC or IPS cells) of 2015 came just yesterday.

A press release from Ohio State University reports that two of its researchers had grown a nearly full-formed human fetal brain.

My initial reaction was, “Wow”, but a very skeptical “wow”.

A few past stem cell claims that turned out to be too good to be true have made me even more cautious and skeptical about what I read, especially if it is a sexy claim without much data.

In this case, the work has not been published. We need to learn more before we can be sure about this fetal brain claim so it’s no time for hype.

The story was picked up like wildfire by the media. That’s the danger with science communication by press release. Maybe it really is a nearly fully formed fetal human brain grown from IPSC in a dish (see image above) or maybe it isn’t.

Update: For some background on solid, organoid, mini-brain stuff, I recommend this.

Professor Rene Anand and colleague Susan McKay reportedly did this newly reported work, and presented it at the 2015 Military Health System Research Symposium in Florida. I was unable to find a copy of the presentation or abstract, which would have been helpful. Without more data, the structure shown in the above image could be just about anything. That’s the thing with organoids; from the outside they don’t look like much.

The Ohio State PR says that Anand is somewhat new to stem cells and yet was able to grow this nearly fully formed fetal human brain.  That would be a rare and impressive accomplishment.

They apparently used an organoid-type approach that is apparently being patented and is proprietary, which also makes it hard to evaluate. An important focus seems to be on commercialization:

“Anand and McKay are co-founders of a Columbus-based start-up company, NeurXstem, to commercialize the brain organoid platform, and have applied for funding from the federal Small Business Technology Transfer program to accelerate its drug discovery applications.”

In addition to analysis by microscopy they reportedly did some kind of gene expression analysis to make the claim that the IPSC fetal brain expresses 99% of the expected genes. I’d like to learn more about that. More from the PR:

“High-resolution imaging of the organoid identifies functioning neurons and their signal-carrying extensions – axons and dendrites – as well as astrocytes, oligodendrocytes and microglia. The model also activates markers for cells that have the classic excitatory and inhibitory functions in the brain, and that enable chemical signals to travel throughout the structure.”

In principle these kinds of analyses would indeed help to identify this tissue as brain-like in nature. Let’s wait and see the data. There is no patent application in the public domain on this that I could find at least, which is too bad as that could have provided more information too.

I also wondered about ethical issues of making a fetal brain. At some point could it start to think? Anand is not concerned according to The Guardian:

“The ethical concerns were non-existent, said Anand. “We don’t have any sensory stimuli entering the brain. This brain is not thinking in any way.”

You sure about that? Have they talked to a bioethicist?

The Guardian reporter Helen Thomson deserves a hat tip on this story. She really did the needed homework on this one unlike the other media stories I found and she reached out to independent scientists who formed a consensus that we can’t be sure of this claim:

Several researchers contacted by the Guardian said it was hard to judge the quality of the work without access to more data, which Anand is keeping under wraps due to a pending patent on the technique. Many were uncomfortable that the team had released information to the press without the science having gone through peer review.

Zameel Cader, a consultant neurologist at the John Radcliffe Hospital, Oxford, said that while the work sounds very exciting, it’s not yet possible to judge its impact. “When someone makes such an extraordinary claim as this, you have to be cautious until they are willing to reveal their data.”

On this and other similar cool science claims made by press release, the best approach is to employ a healthy dose of skepticism. Of course an antidote to skepticism is rigorous peer-reviewed data.

Fantastic organoid voyage: views from inside a mini-organ

Fantastic VoyageDid you ever see the classic sci-fi movie, Fantastic Voyage?

In it, the heroes travel inside of the human body in a craft, observing all kinds of awesome biology in an up close and personal kind of way on route into the brain with the goal to do microsurgery of a sorts.

Even though this movie came out a year before I was born, I saw it later as a kid and found it captivating.

“What if we could travel inside the body or even inside organs?” I thought back then. It seemed like we could learn amazing things first hand.

A new technology called organoids or mini-organs kind of makes this possible today.

In fact, organoids are extra exciting because this technology allows us to make miniature version of organs and then do science on them. The organoids can be differentiated and grown, depending on the type you want to make, from pluripotent or adult stem cells or other sources of tissue.

Even though we cannot literally climb inside to take a look, we can do the next best thing using histology and advanced microscopy even on “living” organoids. In a great piece of science writing, Cassandra Willyard, talks us through all the various new kinds of human organoids: liver, kidney, brain, pancreas, stomach, lung, breast, and the list goes on including “guts” as per the quote from Hans Clevers at right from Willyard’s article. I love this quote.Hans Clevers

If we could shrink ourselves down and literally climb inside a human organoid, what would we see? What amazing things might we report on from this voyage?

In mini-brains we’d see neurons, synapses, glia, oligodendrocytes, and fiber tracts. We even might be witness to electrical activity in this mini-brain that represents actual rudimentary thought of a kind. Imagine seeing that “in person” from the inside.

Cerebral organoidsIn a mini-kidney or liver organoid, we might see all different kinds of cellular and tissue activities. If we dropped the equivalent of a micro bottle of vodka or tiny firecracker inside as a model of injury, we might see the organs kick into action to repair themselves.

In a breast organoid we might see milk production from the inside or the first signs of breast cancer formation. In a mini-lung, we could possibly see lung cancer germinate too or hike around inside airways such as bronchi, bronchioles, and alveoli. A bio-spelunker.

Exploring inside a heart organoid you could feel what it is like to be inside of something very similar to a beating heart. Would you like the rhythm and beat or feel like there’s a constant earthquake?

Inside the organoids in the lab you don’t have to worry about some nasty immune cell trying to knock you off either.

Some of the labs focusing on organoid research have discovered important things about normal human development and disease from this work. The Madeline_Lancasterresearchers include teams from the labs of Drs. Hans Clevers, Jürgen Knoblich, Melissa Little, Takanori Takebe, and a growing number of others. The late Yoshiki Sasai did pioneering work in this area as well.

The postdocs and other trainees in these labs have done work that has changed our visions of what is possible in stem and developmental biology in a dish. For instance, Dr. Madeline Lancaster’s work on mini-brains has opened a lot of minds to all that is possible in brain neuroscience in a dish (see images above of a mini-brain and of Dr. Lancaster at right).

An organoid is not just a model system either, but also might have therapeutic potential. Tissues grown in 3-D that take on the form and function of real human organs even if in miniature form could form the basis of innovative therapies in the future as well.

I would say that so far in 2015 organoids are the most exciting development and some have argued they are most important new thing in the stem cell and developmental biology fields.

For past posts on this blog highlighting organoids you can read here.

New Interview With Masayo Takahashi (高橋 政代) on IPSC Trial: Guest Piece by Michael Cea

By Michael Cea
Stem Cell Analyst & Advocate
(editor’s note: piece was originally posted on Michael’s blog here; follow Michael on Twitter @msemporda)

 

Having followed closely the developments in programs using pluripotent based therapeutics I was fortunate during ISSCR2015 to have the opportunity to sit down with Dr Masayo Takahashi to discuss her pioneering efforts to translate Shinya Yamanaka’s groundbreaking iPS technology for debilitating retinal conditions.Masayo Takahashi

As most everyone is aware, the first iteration of the program, for advanced Wet AMD, has entered the clinic and been safely administered to the first patient – a milestone achievement for the field, which has been widely covered by the media, especially in Japan. However, as I learned first hand, this first step is but a part of a comprehensive strategy to address most retinal diseases by way of various cultured cell transplantation methods, depending on the patient condition – including suspension therapies and multi-layered organoid developed tissue. This was best described by Masayo “what I have said to the Japanese regulators is that ideally we need all cell types – sheets, suspensions, auto, allo – and the surgeons will choose which to use for each patient.”

Monkey stem cell RPEsBefore relaying the key segments of the interview, I wanted to express some thoughts of how practical and committed to the patient Masayo is. Her clinical practice is at the very heart of her professional vision – to bring relief to those that come to her for help. Disappointment again and again in not being able to help drives her passion for new therapies. She is both confident and open to the process that has already taken more than a decade and a half of her research. The goal being, in time, to have all the tools necessary to deliver on the promise to her patients and fulfill on that hope, that is very real and apparent today – something she couldn’t point to just a few short years ago. Her new message is very clear now “visual impairment is not as bad as they think and you can change that world – so there is hope – yes.”

Cheers

Interview:

Q: There is a lot of hype in the field how have you addressed that?

MT: When I started to do the regenerative medicine work the media broadcast our efforts and many patients came and they expected I could help them. But 10 years ago I was very nervous because after hearing the news they were disappointed in front of me so I started to talk to the media and educate. Every month we worked with media so gradually within this period they learned and suppressed their expectations so in Japan the hype isn’t so high anymore.

Q: Does the Internet makes things easier for patients to understand?

MT: People who can connect with the Internet can understand but the older people still don’t have access to the Internet and rely on the newspaper and TV but sometimes they’re informed wrongly as a result so I still struggle.

Q: Is that due to the technical language and complexity of the science?

MT: Common sense is different from the medical reality but the regenerative medicine area is very focused so we can use the media to inform the public correctly. Regenerative medicine won’t cure everything but if you think in a different way you can do many things. The “hope” should be the correct one. People need to learn the way of thinking of the scientists – in Japan people are very clever and gradually they have understood. So if you teach correctly they can understand gradually. It’s important to relay the correct information. Media sometimes tries to simplify as a need or belief in the communication method yet they lose the true message. Stem cells are a specific area with many unknowns – yes – it’s like a “black box.”

Q: You started using ES neuronal cells then moved to iPS and retinal cells

MT: Yes, a little background. I started in 2000 with ES cells and proved in mid-2000 using primate ES cells that we could treat some retinal diseases but we hesitated to move to the clinical stage because the risk of immune rejection. By that time iPS cells came out and I was very happy as I knew the last hurdle would be solved w/ iPS cells so we immediately started research using those cells and after 5 to 6 years of translational research in preclinical studies we started the 1st patient clinical application last September and we will judge the safety and effect 1 year later this September. We announced mid-term results in March and so far we don’t observe any immune rejection without any immunosuppression, which we expected as a result of using autologous iPS cells.

There was a famous paper in the journal Nature that the autologous iPS cells invoked immune rejection in a mouse model but I think the research design wasn’t very good. They transplanted kind of a tumor which would be rejected – not the iPS cells but the tumor.

Q: Was the surgery difficult for the lady (1st patient)?

MT: Yes the surgery was the most risky part. We were worried a little but the procedure was successful with no adverse events so far.

Q: And the next patient?

MT: We tried, we prepared but decided to go quickly to the allogeneic because the cells are already there from Shinya Yamanaka’s cell line stock. He made the 1st iPS cell line and they have come to our lab.

Q: Have they been approved as clinical grade by the Japanese regulators?

MT: Yes but about the protocol, we will apply within this year for approval. We should reapply as it’s allogeneic, different from autologous.

Q: Will this line be available to others?

MT: Shinya Yamanaka will distribute to various centers with one of the institutions being mine. So there will be a Spinal Cord Injury protocol, maybe the Parkinson’s disease trial will go to an allogeneic protocol, the hematopoietic (platelets) will also. So the various protocols will use that cell stock.

Q: Japan is moving very quickly, is that of concern in the community or is that in your mind appropriate?

MT: Most patients are supportive but some people worry we move too fast but really we prepared, labored and accumulated the data and the people who don’t know the whole data usually say you have the risk – that’s very stressful. So actually we don’t care what they say because they don’t know. Maybe it’s a social balance.

Q: Are you taking the trials also outside of your home market?

MT: In the near future. We made a start-up company, Healios, they made an IPO last week, they plan to do a clinical trial in 2 or 3 years time in the US as they need the time to apply the protocol.

Q: I’d like to get your opinion on the use of a monolayer versus the selection of a suspension protocol.

MT: The people who don’t know the disease think the big sheet is the best but there are many, various situations with the disease, various stages, various lesion sizes, so some patients need a large sheet. Ours is 1 x 3mm, people in the US are preparing a 3 x 5mm sheet, so some people don’t need such a big sheet and earlier stage patients don’t require a big incision, so cell suspension is more feasible.

Q: What is your current disease state target?

MT: Advanced Wet AMD and we pull out the neovascular tissue, so a big defect of RPE, and cell sheets are appropriate but if the neovascular damage isn’t large we don’t want to cut and therefore cell suspension is better.

Q: The market is fragmented – is there a synergy with other programs?

MT: The regenerative medicine area is different than the small molecules, it’s more adaptable, so the judgment should return to the clinical scene and not the big pharma. The clinical reality will determine application and the Japanese government knows very well about this issue and we cooperated to make the new law. The Ministry of Health accepted that regenerative medicine is different than small molecules and that all is needed is a small number of patients to get approval, which is a great advance, a revolution.

Q: Is safety sufficient in a small population study?

MT: Of course the accumulation of the animal data needs to be reconfirmed by 10 or so patients for safety but the statistical significance of the efficacy needs more patients to prove the probable efficacy. Companies can sell the products based on smaller numbers so we don’t need big big pharma for promoting regenerative medicine. Companies can sell but they must register and prove efficacy within 7 years with regular exams. Success will be a collaboration between regulatory and academia with insurance reimbursement playing a commercial role which is incredible and kind of a risky law. The background of that is that academia promoted the regenerative medicine mainly so we cooperate very tightly with government and will decide where to provide treatment after approval with rules later.

Q: Do you plan enhanced cell products?

MT: Manipulated cells can work better, yes. So far natural cells are the most feasible, as regulators don’t like manipulated cells or “supercells.” In future but for now natural cells are good.

Q: Can you speak to the adult cell types?

MT: MSCs are safe. iPS/ES are hard to control so are limited to institutes that can maintain them/control them properly but the industrialization for a standard treatment iPS/ES is very good because we can have one lot otherwise many donors and always a lot of changes so that’s not very good industrially. In the future the ES & iPS cells people can control will be the way to industrialize and standardize treatment.

Q: What are your future plans / next steps?

MT: Our next steps are to have combined stem cell sheets – not only RPE but RPE with Photoreceptors and perhaps the vessel layer. Like a dream in our institute, that has a very high developmental biology focus, we talk about the whole retina with blood vessels and will try to deliver the entire retina for retinal disease conditions that destroy all the layers. For now we are working on monolayers, suspension, photoreceptors, combined layers and ganglion etc with 2016 for the allo, 2017 for the Healios suspension and 2018 for the photoreceptors.

Q: Are you collaborating with other institutions – is that part of your plan, UCL for example?

MT: We are not actually collaborating. We have a communication and information exchange, like a think tank. We know how they promote and we are doing very well. We don’t have to hide. They use similar technology adapted from our work. The aim is to make a standard treatment.

Q: Is ownership not an issue?

For the company it’s an issue – I don’t care. Patients don’t care. Healios is very good and they are in contact with the NIH group and the Ali group (UCL) – maybe they collect good procedures from the world.

Q: Are companies in Japan are looking at this sector as a team approach – does this help?

MT: Yes, society of regenerative medicine companies in Japan are maybe 100 companies now under the F.I.R.M association. Fuji, industry, pharma – all diverse companies. Not as a Keiretsu but more an association. Companies are now interested unlike 5 or 6 years ago. I told many companies to help us but they didn’t in the beginning but now they do. The government has helped a lot having supported the industry 10 years ago but they see the reality now as we have the clinical application.

Q: How do you see yourself, as a leader, role model – is there pressure?

MT: Shinya Yamanaka is like an Emperor now – everyone adores him. About the pressure, we have accumulated the data so I don’t fear anything. I have a scheme for 10 years plus and a plan. I know all – from the cells, the pluripotency, genes, animals, disease, patients and social and no worries only a process to move along. There are some against us but if I listen to their talks I’m not convinced by them, I mean persuaded, something wrong in their logic. As a role model – maybe I should behave myself! Patients happiness is what I believe – not papers or money, not interested. Patients first, outpatient clinic is very important to me.

Q: How do you view Lucentis/Eylea?

MT: Wonderful – we saw AMD 25 years ago and there was nothing at all. So we just explained the disease as incurable for 10 years but finally it came out, it was wonderful. We knew AMD very well and knew Lucentis wouldn’t cure everything. The treated patient had 10 injections before surgery and her condition deteriorated from 0.3 to less than 0.1 even though she had the available treatment, so we stabilized her visual acuity with radical treatment without any injection.

By way of disclosure: I have no conflict of interest, financial relationship with anyone or company mentioned in this article.