Knoepfler Lab: Update on our mission and research

Knoepfler LabMany of this blog’s readers ask about what my own lab’s research. What is the focus of the research of the Knoepfler Lab?

You can go check out our lab website, but I thought it might be time to blog about what we are all about as a lab and what we have been up to most recently. I am fortunate to have an exceptional team of researchers in my lab.

Our mission is to advance knowledge toward two main goals: (1) the development of new, safe, and effective stem cell-based regenerative medicine therapies, and (2) catalyzing novel cancer therapies, particularly for childhood brain tumors and other pediatric neuronal cancers. Related to this, we are also investigating how the brain normally grows during development. In short, the research we do mainly converges towards the goal of advancing science to get new stem cell and cancer therapies off the ground.

We are particularly interested in a field of science called epigenetics. We all know about the genome where our genes are coded, but the genome doesn’t do anything without the epigenome, which consists primarily of DNA methylation and histone modifications. Each cell’s epigenetic state orchestrates the genes that are on and off, which in turn collectively controls how that cell behaves (e.g. how a stem cell stays a stem cell or differentiates) or in the case of cancer and other diseases, how it misbehaves. We just recently published a review article on the connections between epigenetics, cancer, and stem cells.

As it turns out, stem cells and cancer cells are unfortunately highly related cell types, perhaps even cellular siblings. For example, we showed in a novel paper last year that the process of cellular reprogramming to make iPS cells is in some ways remarkably similar to the process of turning normal cells into cancer cells. This paper has stirred quite a bit of discussion.

What else have we been up to lately?

Supported by NIH and CIRM, we are working on three main areas and you can see these themes reflected in the lst of our recent publications.

First, we have a long-standing interest in a cancer-related gene called MYC. Some have speculated that every human cancer in one way or another has some problem with MYC, usually too much of it. At the same time, however, Myc proteins are essential for normal stem cell function. As a result Myc ends up being quite the Dr. Jekyll and Mr. Hyde kind of character. As with any molecule or person for that matter, Myc does not act alone. Lately we’ve been getting more interested in a key cofactor of Myc called Miz-1 (see here for more on that). In our newest paper, published just a few days ago, we show how Miz-1 binds to DNA. This should hopefully help the field understand Myc a lot better too.

Second, we are excited about a relatively newer area of epigenetic and chromatin research focused on a molecule called histone variant H3.3. Histones come in different forms and histone variants are cool and interesting because they don’t follow the normal rules for histones. Histone variants such as H3.3 can become part of chromatin (the combination of DNA and histones) basically any time in any kind of cells. For most histones their ability to do that is much more sharply constrained. This makes a variant such as H3.3 far more dynamic and important to decision making processes by cells such as stem cells and cancer cells. In the case of H3.3, two genes make the same identical H3.3 protein. We call these genes A and B, short, for H3f3a and H3f3b. In 2013 we reported in our Bush, et al. paper the phenotype of the first knockout of an H3.3-coding gene in mice with our knockout of the B gene. About half the time, mice lacking the B gene do not make it through development and have a host of problems including an inability to properly segregate their chromosomes during cell division that leads in turn  to DNA damage and apoptosis (cell death). The surviving B knockout mice are pretty much all infertile. It’s notable that mutations in H3.3 occur in humans and are strongly linked to cancer. Last year we also published a review article in Cancer Cell on the H3.3-cancer connection, which involves two particularly disastrous tumors in children called glioblastoma and DIPG.

Third, we are studying two genes that also function in stem cells and cancer called DPPA4 and DPPA2. It is fascinating to think about how certain genes like these, H3.3, and Myc, can function normally in stem cells, but then with a monkey wrench in the system they can cause cancer. In the case of DPPA4 and DPPA2, they have long been known to be important stem cell genes, but it was only in 2013 that our lab discovered and published in the journal Stem Cells that they are also oncogenes. Surprisingly, it is still largely an open question how the Dppa4 and Dppa2 proteins actually work.

Overall one can see that we work at the interface of stem cells, cancer, and developmental tissue growth and investigate how epigenetic machinery orchestrates the regulatory events involved. Finally, we are committed to educational outreach and advocacy for evidence-based innovative cancer treatments and regenerative medicine therapies.

 

 

 

Reflecting on Regenerative Medicine As A Brand

Stem cell-based Regenerative Medicine has huge power for good in the clinic and at the same time great potential for economic development. Those two things go hand in hand.

As I argued in my stem cell book, biotech commercialization of stem cells is not a bad thing, but rather if it is done responsibly it is a good, necessary part of advancing therapies to help patients.

From an economic perspective  stem cell-based Regenerative Medicine is a new, exciting brand.

It’s a brand, but a unique one because it is shared by so many diverse parties and influenced by tens of thousands of people and companies around the world. “Regenerative Medicine” is not owned by any one person or company.

Regenerative Medicine brand

A good analogy would be to “Soft Drinks” rather than to “Coke” or “Pepsi”. Soft Drinks are what we might call an “umbrella brand”. A higher-level brand. It’s important to point out that if “soft drinks” as an umbrella brand get a bad name as being linked to diseases and being harmful to health, for example, it is bad for all soft drink companies…or to extend the analogy all car companies or all airline companies, etc. .

The same kind of thing is true for Regenerative Medicine as an umbrella brand. If some folks give it a bad name, it hurts everyone with an interest in the brand including current and future patients.

There is a shared collective interest in promoting this brand and enhancing the public’s knowledge and positive, evidence-based perceptions of Regenerative Medicine. Of course there are specific organizations with the words “Regenerative” and “Medicine” in their name such as the great journal Regenerative Medicine (disclosure, I’m on the editorial board), CIRM, the Alliance for Regenerative Medicine (ARM) and many others so perhaps the stakes are highest for them on this brand, but it still has a powerful, more global impact. Without commercialization of stem cells we collectively cannot get safe, effective, evidence-based therapies to patients.

Our brand “Regenerative Medicine” faces some serious challenges even as it advances. These challenges include threats to the perception of the brand as scientific and trustworthy. These come from scandals such as STAP and others that do not reflect the ethos of our field but disproportionately and negatively influence the Regenerative Medicine brand.

Publicity is good for Regenerative Medicine, but hype isn’t so we need to draw a line. As much as we all want to spread the word about stem cells and how exciting they are, there is such a thing as going too fast, cutting corners, or hype.

Dubious stem cell clinics are another threat to the Regenerative Medicine brand. I don’t think the legit stem cell/regenerative medicine field is doing enough to counter these clinics as they spread like mushrooms all over the world including in the US.

As much as there are threats and challenges to Regenerative Medicine, it is also an incredibly, exciting and even revolutionary time for this brand and its associated fields of science. I usually don’t think of Regenerative Medicine as a brand, but I believe that now and then viewing it from that perspective is a helpful, healthy exercise.

Disclosure–I own no stock or positions in stem cell or regen med biotechs.

Some cool recent stem cell papers: recommended reading

What have been some recent stem cell and/or regenerative medicine papers that are worth some extra thought and reading?

There have been some cool ones.

There was of course the very important Mitalipov group paper comparing NT hESCs to IVF hESCs and hIPSCs. See my review here.

There was a great paper on the role of HDACs in mESCs.

A paper reporting making endothelial and hematopoietic cells from pluripotent stem cells with a combination of GATA2 and other individual transcription factors.

In vivo reprogramming in pigs reportedly leads to transient production of pacemaker cells in hearts.

Planarian worms have the remarkable ability to regrow entire worms when sliced into tiny pieces and they do so via pluripotent stem cells called neoblasts. A new paper demonstrates that not all neoblasts are created equal and different clones exhibit specific fate preferences.

What recent papers would you recommend on stem cells or regenerative medicine?

 

StemCells, Inc. Faces Lawsuit With Serious Allegations

stemcellsinc-logoStemCells, Inc. is one of those stem cell-related biotech companies that we in the field hope will become a big success and help many patients in the future via stem cell technology.

There are a lot of obstacles facing such companies. Some are privately held, while others such as StemCells, Inc. are publicly traded (stock symbol STEM). Unfortunately, StemCells, Inc. has had to face two rather serious problems in the last few weeks.

First, former CIRM President Alan Trounson joined the leadership of StemCells, Inc. only days after leaving CIRM despite the fact that CIRM had granted the company almost $20 million during Trounson’s tenure as President. This move has faced criticism (e.g. see here) because of the appearance of a potentially serious conflict of interest. It appears CIRM was not aware of Trounson’s joining the StemCells, Inc. board until the news came into the public domain.

Second, today Courthouse News Service announced that a former StemCells, Inc. manager, Rob Williams, has filed suit against the company. David Jensen has also reported on this breaking case here and here.

Williams alleges potentially serious problems with the company’s procedures. He also claims wrongful termination and retaliation. The latter allegations center on the claim that once he made upper management aware of his concerns about the stem cell lines and manufacturing practices that he was terminated shortly thereafter. The actuall full lawsuit file can be read here (PDF; hat tip to Jensen).

From the suit, quoted on Jensen’s blog, come very serious and as yet unsubstantiated accusations:

“’Shortly after beginning his employment, plaintiff noted poor sterile technique, failure to adhere to current Good Manufacturing Practices in the company’s manufacturing process, and substantial deficiencies in the company’s Manual Aseptic Processing of HuCNS-SC (Human Central Nervous System Stem Cells) cell lines – failure and deficiencies that put patients at risk of infection or death during ongoing clinical trials,’ Williams says.

Update: StemCells, Inc. via Jensen’s blog, has issued a statement denying the charges:

“The Company has reviewed the complaint filed by Mr. Williams, a former employee whose employment was terminated for performance deficiencies, and finds no merit to the allegations.”

 

Of course, as with any ongoing litigation, those of us who are not parties to the case do not know the facts and StemCells, Inc. will certainly have its side to this case. Therefore, I’d encourage people not to rush to judgment. However, this is a concerning development for the company and the stem cell field.

Top 5 possible natural stem cell boosts

Stem Cell BoostHow might we all boost our own stem cells?

If possible isn’t that a better, simpler, & safer idea than getting a transplant of stem cells?

Think of it as preventative medicine via stem cells.

It’s not a sure thing by any means. And, yeah, it is not as simple as asking for a boost in your Jamba Juice (see at right).

However, below are five possible simple ways that research suggests theoretically might be helpful to give your existing so-called endogenous stem cells a boost. You can also read more on this in my new stem cell book.

Important: consult with your doctor before considering any of these ideas. This blog post is not meant as medical advice.

1. Exercise

The human body seems designed to increase stem cell numbers when we are more active. This makes great sense if you consider that the more active that we are the more new cells that we’ll need as we are likely to lose more of our older cells by exercising. Here are two papers backing up the idea of exercise boosting our stem cell numbers.

2. Caloric restriction and fasting

An article recently came out saying that fasting boosts stem cell numbers. The team from USC found that even just a few days of fasting increased the number of stem cells in our blood system. This potential connection between fasting and stem cell numbers also makes sense as our body probably needs to be more efficient at times of low food availability and boost resistance to infection.

3. Tai chi

Researchers in China have reported that people who practice the martial art Tai Chi saw a several-fold boost in their stem cell populations (by which they meant a specific type of cell called a “Progenitor CD34+Cells” cell. This seems a little too good to be true in terms of magnitude, but could fit in with the exercise boost discussed above.

4. Sleep

Although I wrote earlier about how activity could boost stem cell levels, it also kind of makes sense that stem cells may do their thing while we are asleep. Stem cell science also supports this idea as well.

5. Protect yourself and your stem cells from radiation

When you read this you probably are thinking of dental or chest x-rays or CT scans, but I think a far more important source of radiation for most of us is UV light from the sun.

It is smart to protect your skin stem cells. Become an educated user of sunscreens and about sun exposure. Their use is complex and in fact may be harmful if misused as most of us do. In any case, the best protection from skin cancer is shade or if you have to be out in the sun, clothing. Do not let sunscreen increase your sun exposure dramatically or its use will backfire.

Finally, something that is not recommended. Stem cell supplements are not of any use based on today’s clearest evidence. They are at best a huge waste of money and at worst a risk to your health.