CIRM-Funded Scientists Build a Better Neuron; Gain New Insight into Motor Neuron Disease

Each individual muscle in our body—no matter how large or how small—is controlled by several types of motor neurons. Damage to one or more types of these neurons can give rise to some of the most devastating motor neuron diseases, many of which have no cure. But now, stem cell scientists at UCLA have manufactured a way to efficiently generate motor neuron subtypes from stem cells, thus providing an improved system with which to study these crucial cells.

“Motor neuron diseases are complex and have no cure; currently we can only provide limited treatments that help patients with some symptoms,” said senior author Bennett Novitch, in a news release. “The results from our study present an effective approach for generating specific motor neuron populations from embryonic stem cells to enhance our understanding of motor neuron development and disease.”

Normally, motor neurons work by transmitting signals between the brain and the body’s muscles. When that connection is severed, the individual loses the ability to control individual muscle movement. This is what happens in the case of amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig’s disease.

These images reveal the significance of the 'Foxp1 effect.' The Foxp1 transcription factor is crucial to the normal growth and function of motor neurons involved in limb-movement.

These images reveal the significance of the ‘Foxp1 effect.’ The Foxp1 transcription factor is crucial to the normal growth and function of motor neurons involved in limb-movement.

Recent efforts had focused on ways to use stem cell biology to grow motor neurons in the lab. However, such efforts to generate a specific type of motor neuron, called limb-innervating motor neurons, have not been successful. This motor-neuron subtype is particularly affected in ALS, as it supplies nerves to the arms and legs—the regions usually most affected by this deadly disease.

In this study, published this week in Nature Communications, Novitch and his team, including first author Katrina Adams, worked to develop a better method to produce limb-innervating motor neurons. Previous efforts had only had a success rate of about 3 percent. But Novitch and Adams were able to boost that number five-fold, to 20 percent.

Specifically, the UCLA team—using both mouse and human embryonic stem cells—used a technique called ‘transcriptional programming,’ in order to coax these stem cells into become fully functional, limb-innervating motor neurons.

In this approach, which was funded in part by a grant from CIRM, the team added a single transcription factor (a type of protein that regulates gene function), which would then guide the stem cell towards becoming the right type of motor neuron. Here, Novitch, Adams and the team used the Foxp1 transcription factor to do the job.

Normally, Foxp1 is found in healthy, functioning limb-innervating motor neurons. But in stem cell-derived motor neurons, Foxp1 was missing. So the team reasoned that Foxp1 might actually be the key factor to successfully growing these neurons.

Their initial tests of this theory, in which they inserted Foxp1 into a developing chicken spinal cord (a widely used model for neurological research), were far more successful. This result, which is not usually seen with most unmodified stem-cell-derived motor neurons, illustrates the important role played by Foxp1.

The most immediate implications of this research is that now scientists can now use this method to conduct more robust studies that enhance the understanding of how these cells work and, importantly, what happens when things go awry.

Gene Therapy Beats Half-Matched Stem Cell Transplant in Side-by-Side Comparison to Treat ‘Bubble Baby’ Disease

If you are born with Severe Combined Immunodeficiency (SCID), your childhood is anything but normal. You don’t get to play with other kids, or be held by your parents. You can’t even breathe the same air. And, without treatment, you probably won’t live past your first year.

The bubble boy.  Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

The bubble boy. Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

This is the reality of SCID, also called “Bubble Baby” disease, a term coined in the 1970s when the only way to manage the disease was isolating the child in a super clean environment to avoid exposure to germs. The only way to treat the disorder was with a fully matched stem cell transplant from a bone marrow donor, ideally from a sibling. But as you may have guessed, finding a match is extraordinarily rare. Until recently, the next best option was a ‘half-match’ transplant—usually from a parent. But now, scientists are exploring a third, potentially advantageous option: gene therapy. Late last year, we wrote about a promising clinical trial from UCLA researcher (and CIRM Grantee) Donald Kohn, whose team effectively ‘cured’ SCID in 18 children with the help of gene therapy. Experts still consider a fully matched stem cell transplant to be the gold standard of treatment for SCID. But are the second-tier contenders—gene therapy and half-matched transplant—both equally as effective? Until recently, no one had direct comparison. That all changes today, as scientists at the Necker Children’s Hospital in Paris compare in the journal Blood, for the first time, half-matched transplants and gene therapy—to see which approach comes out on top. The study’s lead author, Fabien Touzot, explained the importance of comparing these two methods:

“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”

So the team monitored a group of 14 SCID children who had been treated with gene therapy, and compared them to another group of 13 who had received the half-matched transplant. And the differences were staggering. Children in the gene therapy group showed an immune system vastly improved compared to the half-matched transplant group. In fact, in the six months following treatment, T-cell counts (an indicator of overall immune system health) rose to almost normal levels in more than 75% of the gene therapy patients. In the transplant group, that number was just over 25%. The gene therapy patients also showed better resilience against infections and had far fewer infection-related hospitalizations—all indictors that gene therapy may in fact be superior to a half-matched transplant. This is encouraging news say researchers. Finding a fully matched stem cell donor is incredibly rare. Gene therapy could then give countless families of SCID patients hope that their children could lead comparatively normal, healthy lives. “Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” explained Touzot. “These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach.” Hear more about how gene therapy could revolutionize treatment strategies for SCID in our recent interview with Donald Kohn:

Stem Cell Scientists Reconstruct Disease in a Dish; Gain Insight into Deadly Form of Bone Cancer

The life of someone with Li-Fraumeni Syndrome (LFS) is not a pleasant one. A rare genetic disorder that usually runs in families, this syndrome is characterized by heightened risk of developing cancer—multiple types of cancer—at a very young age.

People with LFS, as the syndrome is often called, are especially susceptible to osteosarcoma, a form of bone cancer that most often affects children. Despite numerous research advances, survival rates for this type of cancer have not improved in over 40 years.

shutterstock_142552177 But according to new research from Mount Sinai Hospital and School of Medicine, the prognosis for these patients may not be so dire in a few years.

Reporting today in the journal Cell, researchers describe how they used a revolutionary type of stem cell technology to recreate LFS in a dish and, in so doing, have uncovered the series of molecular triggers that cause people with LFS to have such high incidence of osteosarcoma.

The scientists, led by senior author Ihor Lemischka, utilized induced pluripotent stem cells, or iPSCs, to model LFS—and osteosarcoma—at the cellular level.

Discovered in 2006 by Japanese scientist Shinya Yamanaka, iPSC technology allows scientists to reprogram adult skin cells into embryonic-like stem cells, which can then be turned into virtually any cell in the body. In the case of a genetic disorder, such as LFS, scientists can transform skin cells from someone with the disorder into bone cells and grow them in the lab. These cells will then have the same genetic makeup as that of the original patient, thus creating a ‘disease in a dish.’ We have written often about these models being used for various diseases, particularly neurological ones, but not cancer.

“Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer,” said lead author and Mount Sinai postdoctoral fellow Dung-Fang Lee in today’s press release.

The team’s research centered on the protein p53. P53 normally acts as a tumor suppressor, keeping cell divisions in check so as not to divide out of control and morph into early-stage tumors. Previous research had revealed that 70% of people with LFS have a specific mutation in the gene that encodes p53. Using this knowledge and with the help of the iPSC technology, the team shed much-needed light on a molecular link between LFS and bone cancer. According to Lee:

“This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place.”

Specifically, the team discovered that the ultimate culprit of LFS bone cancer is an overactive p53 gene. Too much p53, it turns out, reduces the amount of another gene, called H19. This then leads to a decrease in the protein decorin. Decorin normally acts to help stem cells mature into healthy, bone-making cells, known as osteoblasts. Without it, the stem cells can’t mature. They instead divide over and over again, out of control, and ultimately cause the growth of dangerous tumors.

But those out of control cells can become a target for therapy, say researchers. In fact, the team found that artificially boosting H19 levels could have a positive effect.

“Our experiments showed that restoring H19 expression hindered by too much p53 restored “protective differentiation” of osteoblasts to counter events of tumor growth early on in bone cancer,” said Lemischka.

And, because mutations in p53 have been linked to other forms of bone cancer, the team is optimistic that these preliminary results will be able to guide treatment for bone cancer patients—whether they have LFS or not. Added Lemischka:

“The work has implications for the future treatment or prevention of LFS-associated osteosarcoma, and possibly for all forms of bone cancer driven by p53 mutations, with H19 and p53 established now as potential targets for future drugs.”

Learn more about how scientists are using stem cell technology to model disease in a dish in our special video series: Stem Cells In Your Face:

Cancer Cells Mimic Blood Vessels to Colonize the Body’s Farthest Reaches

Scientists at Cold Spring Harbor Laboratory have just uncovered the latest dirty trick in the cancer playbook—one that spurs the cancer cells to spread throughout the body and evade treatment. But importantly, they believe they may have found a way to counter it.

Reporting today in the journal Nature, Cold Spring Harbor researchers describe how tumor cells can form tubular networks that mimic blood vessels. It is this mimicry, the team argues, that plays a key role in helping the cancer spread throughout the body—and a significant hurdle to successfully treating the disease.

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Using mouse models of breast cancer, the team—led by Simon Knott—identified this phenomenon, called ‘vascular mimicry,’ and revealed that two genes, called Serpine2 and Slpi, were driving it. Made up of tumor cells literally stacked together, these tubular networks allowed oxygen and other nutrients to reach far-flung tumor cells throughout the body. This kept the tumor cells healthy, and helped them spread.

In today’s press release, Knott explained his initial reactions to this critical discovery:

“It’s very neat to watch and see cells evolve to have these capacities, but on the other hand it’s really scary to think that these cells are sitting there in people doing this.”

In laboratory experiments, the team found that boosting levels of Serpin2 and Slpi boosted the cancer’s ability to build these networks. Conversely, shutting down these two genes appeared to do the opposite. Knott argues that targeting the proteins that these two genes produce, as a way of shutting them off, may be a winning strategy:

“Targeting them might provide therapeutic benefits,” said Knott, “but we’re not sure yet.”

Indeed, research efforts over the past decade or more have tried to curb the production of these tubular networks of tumor cells, but with limited success. These drugs, called angiogenesis inhibitors, may not have worked as well as originally hoped because the underlying mechanism that creates this vascular mimicry—namely the genes Serpin2 and Slpi—was not targeted. Postdoctoral researcher Elvin Wagenblast, the paper’s first author, thinks they might have more success now:

“Maybe by targeting angiogenesis and also vascular mimicry at the same time we might actually have a better benefit in the clinic in the long run.”

This strategy is ultimately the goal of the team, but much work remains. Their most immediate next steps are to understand the process by which tumor cells pass through these tubular networks and infiltrate new areas of the body. But armed with this new-found knowledge of vascular mimicry, these and other researchers may be well on their way to outsmarting cancer, at least some of the time.

Building a Better Needle: CIRM-Funded Invention Gets Cells Into Brain More Safely, Efficiently

If NASA’s billion dollar Mars rovers deployed a bunch of dollar store party balloons to cushion the moment of impact, the mission would fail miserably. Likewise, the many years and millions of dollars spent on developing a stem cell-based therapy could be all for naught if the delivery of those precious cells into patients used cheap, inefficient tools.

That’s the subject of a recent TV interview with George Yu, who is CEO of Accurexa, a company that is developing and commercializing a novel syringe and needle device that could dramatically improve the delivery of cell therapies to the brain. The device was invented by UCSF neurosurgeon Daniel Lim with the support of a CIRM Tools and Technologies grant.

“So [Dr. Lim] participated in a phase 1 trial a few years ago where he was asked to deliver stem cell[-derived cells] to the brain and he didn’t really have adequate tools to do that, “ Yu explained in his interview with the New York-based finance and business TV program, New to the Street.

“The company that manufactured the stem cells spent millions of dollars in research but then they gave [Dr. Lim] a syringe and a needle that literally costs a couple of dollars. When he used that syringe and needle, which is a straight needle and injected those cells into the brain he actually saw a substantial amount of cells coming to the surface of the brain, which we call reflux, and that’s the reason he said there must be something better than this. And he applied for a grant, he got funded, and he invented the device. “

Not only does the standard straight syringe and needle cause a loss of transplanted cells due to reflux it also requires multiple injections in order to properly distribute the cell therapy in the brain. And with each injection, healthy brain tissue is damaged and increases the risk of stroke.

The Branched Point Device allows a well distributed cell transplantation into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

The Branched Point Device allows a well distributed transplantation of cells into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

Lim’s invention, called a Branched Point Device, avoids both cell reflux and the need for multiple injections. Instead of coming straight out of the needle tip, the cells are delivered through an opening that’s positioned on the side of the needle. So rather than re-injecting the needle, it’s incrementally rotated to deliver the cells in a different direction. With the use of a catheter that pokes through the needle, the cells can be distributed around the needle at different depths in a radial pattern much like the branches of a tree.

Use of the device in clinical trials may soon become a reality based on Yu’s comments in the interview:

“We’ve mostly completed our testing and the design of the device and we’re in the late stage of preparing a 510k submission to the FDA. So we expect that to happen this year. And once it’s FDA approved we can potentially sell the device.”

And because CIRM funded the development of this invention, the State of California is entitled to share in licensing revenue arising from the invention. Better still, the use of the device in clinical trials could provide more consistent, reliable results and a faster path to approval for stem cell-based therapies for neurodegenerative diseases like Parkinson’s.

Breast Cancer Tumors Recruit Immune Cells to the Dark Side

We rely on our immune system to stave off all classes of disease—but what happens when the very system responsible for keeping us healthy turns to the dark side? In new research published today, scientists uncover new evidence that reveals how breast cancer tumors can actually recruit immune cells to spur the spread of disease.

Some forms of breast cancer tumors can actually turn the body's own immune system against itself.

Some forms of breast cancer tumors can actually turn the body’s own immune system against itself.

Breast cancer is one of the most common cancers, and if caught early, is highly treatable. In fact, the majority of deaths from breast cancer occur because the disease has been caught too late, having already spread to other parts of the body, a process called ‘metastasis.’ Recently, scientists discovered that women who have a heightened number of a particular type of immune cells, called ‘neutrophils,’ in their blood stream have a higher chance of their breast cancer metastasizing to other tissues. But they couldn’t figure out why.

Enter Karin de Visser, and her team at the Netherlands Cancer Institute, who announce today in the journal Nature the precise link between neutrophil immune cells and breast cancer metastasis.

They found that some types of breast tumors are particularly nefarious, sending out signals to the person’s immune system to speed up their production of neutrophils. And then they instruct these newly activated neutrophils to go rogue.

Rather than attack the tumor, these neutrophils turn on the immune system. They especially focus their efforts at blocking T cells—the type of immune cells whose job is normally to target and attack cancer cells. Further examination in mouse models of breast cancer revealed a particular protein, called interleukin 17 (or IL17) played a key role in this process. As Visser explained in today’s news release:

“We saw in our experiments that IL17 is crucial for the increased production of neutrophils. And not only that, it turns out that this is also the molecule that changes the behavior of the neutrophils, causing them to become T cell inhibitory.”

The solution then, was clear: block the connection, or pathway, between IL17 and neutrophils, and you can thwart the tumor’s efforts. And when Visser and her team, including first author and postdoctoral researcher Seth Coffelt, did this they saw a significant improvement. When the IL17-neutrophil pathway was blocked in the mouse models, the tumors failed to spread at the same rate.

“What’s notable is that blocking the IL17-neutrophil route prevented the development of metastases, but did not affect the primary tumor,” Visser added. “So this could be a promising strategy to prevent the tumor from spreading.”

The researchers are cautious about focusing their efforts on blocking neutrophils, however, as these cells are in and of themselves important to stave off infections. A breast cancer patient with neutrophil levels that were too low would be at risk for developing a whole host of infections from dangerous pathogens. As such, the research team argues that focusing on ways to block IL17 is the best option.

Just last month, the FDA approved an anti-IL17 based therapy to treat psoriasis. This therapy, or others like it, could be harnessed to treat aggressive breast cancers. Says Visser:

“It would be very interesting to investigate whether these already existing drugs are beneficial for breast cancer patients. It may be possible to turn these traitors of the immune system back towards the good side and prevent their ability to promote breast cancer metastasis.”

Goodnight, Stem Cells: How Well Rested Cells Keep Us Healthy

Plenty of studies show that a lack of sleep is nothing but bad news and can contribute to a whole host of health problems like heart disease, poor memory, high blood pressure and obesity.

HSCs_Sleeping_graphic100x100

Even stem cells need rest to stay healthy

In a sense, the same holds true for the stem cells in our body. In response to injury, adult stem cells go to work by dividing and specializing into the cells needed to heal specific tissues and organs. But they also need to rest for long-lasting health. Each cell division carries a risk of introducing DNA mutations—and with it, a risk for cancer. Too much cell division can also deplete the stem cell supply, crippling the healing process. So it’s just as important for the stem cells to assume an inactive, or quiescent, state to maintain their ability to mend the body. Blood stem cells for instance are mostly quiescent and only divide about every two months to renew their reserves.

Even though the importance of this balance is well documented, exactly how it’s achieved is not well understood; that is, until now. Earlier this week, a CIRM-funded research team from The Scripps Research Institute (TSRI) reported on the identification of an enzyme that’s key in controlling the work-rest balance in blood stem cells, also called hematopoietic stem cells (HSCs). Their study, published in the journal Blood, could point the way to drugs that treat anemias, blood cancers, and other blood disorders.

Previous studies in other cell types suggested that this key enzyme, called ItpkB, might play a role in promoting a rested state in HSCs. Senior author Karsten Sauer explained their reasoning for focusing on the enzyme in a press release:

“What made ItpkB an attractive protein to study is that it can dampen activating signaling in other cells. We hypothesized that ItpkB might do the same in HSCs to keep them at rest. Moreover, ItpkB is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

To test their hypothesis, the team studied HSCs in mice that completely lacked ItpkB. Sure enough, without ItpkB the HSCs got stuck in the “on” position and continually multiplied until the supply of HSCs stores in the bone marrow were exhausted. Without these stem cells, the mice could no longer produce red blood cells, which deliver oxygen to the body or white blood cells, which fight off infection. As a result the animals died due to severe anemia and bone marrow failure. Sauer used a great analogy to describe the result:

“It’s like a car—you need to hit the gas pedal to get some activity, but if you hit it too hard, you can crash into a wall. ItpkB is that spring that prevents you from pushing the pedal all the way through.”

With this new understanding of how balancing stem cell activation and deactivation works, Sauer and his team have their sights set on human therapies:

“If we can show that ItpkB also keeps human HSCs healthy, this could open avenues to target ItpkB to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

The best tools to be the best advocate

It’s hard to do a good job if you don’t have the right tools. And that doesn’t just apply to fixing things around the house, it applies to all aspects of life. So, in launching our new website this week we didn’t just want to provide visitors to the site with a more enjoyable and engaging experience – though we hope we have done that – we also wanted to provide a more informative and helpful experience. That’s why we have created a whole new section call the Patient Advocate Toolbox. shutterstock_150769385

The goal of the Toolbox is simple; to give patients and patient advocates help in learning the skills they need to be as effective as possible about raising awareness for their particular cause.

As an advocate for a disease or condition you may be asked to speak at public events, to be part of a panel discussion at a conference, or to do an interview with a reporter. Each of those requires a particular set of skills, in areas that many of us may have little, if any, experience in.

That’s where the Toolbox comes in. Each section deals with a different opportunity for you to share your story and raise awareness about your cause.

In the section on “Media Interviews”, for example, we walk you through the things you need to think about as you prepare to talk to a reporter; the questions to ask ahead of time, how to prepare a series of key messages, even how to dress if you are going to be on TV. The idea is to break down some of the mystique surrounding the interview, to let you know what to expect and to help you prepare as fully as possible.

If you are going to be asked questions about stem cell research there’s a section in the Toolbox called “Jargon-Free Glossary” that translates scientific terms into every-day English, so you can talk about this work in a way that anyone can understand.

There’s also a really wonderfully visual infographic on the things you need to know when thinking about taking part in a clinical trial. It lays out in simple, easy-to-follow steps the questions you should ask, the potential benefits and problems of being in a trial, including the risks of going overseas for unproven therapies.

The Toolbox is by no means an exhaustive list of all the things you will need to know to be an effective advocate, either for yourself or a friend or loved one, but it is a start.

We would love to hear from you on ways we can improve the content, on other elements that would be useful to include, on links to other sites that you think would be helpful to add. Our goal is to make this as comprehensive and useful as possible. Your support, your ideas and thoughts will help us do just that. If you have any comments please send them to info@cirm.ca.gov

Thomas Carlyle, the Scottish philosopher, once wrote: “Man is a tool-using animal. Without tools he is nothing, with tools he is all.” That’s why we want to give you the tools you need to be as effective as you can. Because the more powerful your voice, the more we all benefit.

CIRM Launches New and Improved Website

CIRM has experienced many exciting changes over the past year: we’ve welcomed a new president, revamped our blog and—perhaps most importantly—announced a radical overhaul in how we fund stem cell research with the launch of CIRM 2.0. That’s not even mentioning the 11 projects we are now funding in clinical trials.

And now, we’d like to announce our latest exciting change: we’ve given our website a facelift that reflects the new CIRM 2.0. Allow us to introduce you to the new digital home of California’s Stem Cell Agency:

CIRM Homepage

Our mission—accelerating stem cell treatments to patients with unmet medical needs—informs everything we do here at CIRM, and the redesign of our website is no different. In improving our site, we hope to better serve two important audiences who are critical in us achieving our mission:

  • Current and potential grantees from research institutions and industry; and
  • Patients, patient advocates and the public at large who are helping others understand how CIRM-funded scientists are turning stem cells into cures.

We are also using this opportunity to improve the way we are viewed on mobile devices. With up to 40 percent of our visitors coming to cirm.ca.gov via a smartphone or tablet, we wanted to create a superior mobile user experience—so that people can easily access the same content whether they are at home or on the go.

We began this project just a few short months ago, and are thankful for a stellar team of in-house staff and contractors who each dove in to lend a hand. We are especially grateful to Radiant, who worked with CIRM to develop an improved design and navigation.

CIRMnew_Logo_Orange_1300x533

As part of the process of updating the website we also took the opportunity to update our logo. The old logo was ten years old, an eternity in the age of the Internet. We wanted something that reflected our new streamlined approach to funding, something that was visually appealing and contemporary and something that immediately connected the viewer to who we are and what we do. We hope you like it.

So please, take a look around at the new cirm.ca.gov—we hope you enjoy using it as much as we enjoyed creating it for you. And of course if you have any thoughts or suggestions on how we can improve this even more we’d love to hear from you in the comments below.