A Foray Into Science

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In a 700-acre enclosure within Ol Pejeta Conservancy Park, roam three northern white rhinoceroses – Sadu, Najin and Fatu. Due to heavy poaching and loss of habitat, these three white rhinos are the last of their kind. Conservation efforts brought back the numbers of their cousin, the southern white rhinos, but unfortunately the same can’t be said for them.

And with reproduction efforts unsuccessful, the future of the northern white rhinoceros look grim. An unfortunate reality shared by many other endangered species.

And while conservation efforts provide hope to save these endangered species, a different approach offers new hope for the future of endangered animals. Covered in A New Hope For Conservation Part 1, a clouded leopard cub was birthed through by artificial insemination using frozen/thawed semen. A first for the vulnerable species. In the bigger outlook of conservation, it was a step towards a different route of preservation. Beyond artificial insemination, there lies the possibility of using induced pluripotent stem (iPS) cells to augment breeding populations.  

In 2016, Katsuhiko Hayashi at Kyushu University in Japan successfully engineered artificial egg cells from reprogrammed mouse skin cells. The egg cells were used to give birth to healthy and fertile pups. His lab is part of a consortium attempting to apply this breakthrough to the northern white rhinoceros. This consortium of conservation and scientific organizations are attempting to produce eggs from iPS cells converted to gametes, which would then be fertilized in vitro with frozen semen. The fertilized egg would then be carried to term by a closely related animal, possibly a south white rhinoceros.

And while this effort is underway, similar efforts are underway to collect cells and DNA from endangered species. The Frozen Ark is an organization set on collecting and cataloguing the DNA and cells of endangered animals before they are extinct. Started by Professor Bryan Clarke and his wife Dr. Ann Clarke, the two were inspired after witnessing the extinction of a hundred species of snails during a study on evolution biology. Today, with over 700 samples stored from an assortment of endangered animals, the Frozen Ark continues to collect samples in anticipation of a future where conservation efforts may depend DNA cellular samples.

These organizations and their efforts will be vital as the extinction rate continues to increase. These new ideas and breakthroughs, partnered with ongoing conservation efforts, may yet provide salvation for endangered animals.

Stem Cells on my Mind

Calling the brain complex is an understatement. Consisting of 100 billion neurons, each of which is connected to as many as 10,000 other neurons, we are just starting to unravel the many functions of the brain in health and disease. One obstacle to studying the brain and developing treatments for its many diseases is the fact that neurons, like cardiomyocytes, don’t divide. The brain is incredibly plastic and is capable of forming new connections between existing neurons, but they don’t proliferate which makes them difficult to study in the lab. Much research has been done using mouse cells, but for a long time there wasn’t a good way to study human microglial cells. Recent research has focused on reprogramming already differentiated skin cells (“fibroblasts”) into a variety of neural cell types. These techniques can help us better understand the brain, and maybe even treat some of its most devastating diseases.

Microglial Cells: Custodians of the Brain

Microglial cells are a type of immune cell found in the brain. They are crucial when it comes to brain development, plasticity, and maintaining the proper conditions for neurons to function. Additionally, they have been found to play a role in the progression of diseases, such as Alzheimer’s disease. These progressive neurodegenerative diseases are difficult to study in animal models, partly due to differences in biology and partly due to the fact that they develop after many decades. A recent paper published by Abud et al. [1] was able to create microglial cells from humans using induced pluripotent stem cells (iPSCs). The researchers took samples of skin and blood cells from human donors and reprogrammed them into iPSCs. They then used a differentiation protocol they developed using a specific combination of proteins, hormones, and other soluble factors to guide the iPSCs into forming microglial cells. These cells resemble native microglial cells in many ways and naturally integrate into the 3D structure of both brain organoid structures (Fig. 1) and in vivo in the brains of mice.

Figure 1: 3D brain organoid tissue. Microglial cells (green) spread throughout a 3D brain organoid tissue in a dish. Blue indicates a structural protein representing neurons and red indicates astrocytes, another type of support cell in the brain. (Credit: Abud et al.)

New Treatments for Brain Cancer

                  Cancers of the brain, such as glioblastoma, are devastating. They are difficult to treat, and the side effects of treatment, including chemotherapy and surgery, can be as difficult to deal with as the cancer itself. Finally, glioblastoma progresses extremely quickly and the average survival is only about a year. New treatments to improve survival and lessen side effects are desperately needed. Several years ago, researchers discovered that neural stem cells will migrate to sites of glioblastoma. They can be engineered to produce various proteins that will kill the cells nearby, which makes this an attractive method for non-invasively treating brain cancer. However, native neural stem cells are difficult to find. Until now, researchers had to reprogram cells into iPSCs which could then be differentiated into neural stem cells, a time-consuming process. In a recent paper, Bagó et al. developed a streamlined process for producing patient-specific neural stem cells [2]. They directly differentiated (transdifferentiated) skin cells from human donors into neural stem cells, using one of the 4 factors needed to create iPSCs. By skipping the iPSC step, they can create neural stem cells in only 4 days. This speed is critical when it comes to a fast-moving cancer like glioblastoma. The neural stem cells they created were engineered with a protein to kill the cancer cells and they cells migrated to the site of glioblastoma and slowed the progression of tumor growth (Fig. 2).

Figure 2: A mouse model of glioblastoma. In mice treated with the control cells (top row), tumors grew significantly over 20 days (red). In the treatment group (bottom row), the tumor growth was greatly inhibited. (Credit: Bagó et al.)

                  Considering how unique our brains are to making us who we are, it makes sense that it would be one of the first areas to benefit from the development of personalized medicine. In time, we may come to a deeper understanding of one of nature’s greatest mysteries, and the possibilities are mind-boggling.

[1] Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH . . . Blurton-Jones M. (2017).  iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron.

[2] Bagó JR, Okolie O, Dumitru R, Ewend MG, Parker JS . . . Hingtgen SD. (2017). Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Science Translational Medicine.

A Foray into Science: Importance of iPS Cells

The discovery of induced Pluripotent Stem (iPS) cells over a decade ago was a hallmark for regenerative medicine. *To learn more about stem cells, read Alex’s Stem Cells: A Primer*. With the use of iPS cells there is seemingly no ceiling on the potential of personalized medicine. And while we wait for these clinical trials to advance to treatments, iPS cells have made an impact in a different way.

Research labs have used iPS cells to model and research human diseases and screening drugs. This is especially true with the research of human development and neurological diseases.

Labs have successfully grown mini brains from skin cells; studying the development of the human brain and what leads to neurological diseases like autism and schizophrenia. Urine cells, collected from individuals with Down syndrome, are turned into iPS cells to study the neurological disorder. This non-invasive collection procedure allows for a greater number of samples to study from vulnerable populations, such as children and individuals with intellectual disability.

Scientists have also created banks of “organoids,” mini stomachs, kidneys, livers and more to study human development and how diseases are created.

  • The mini guts have proved to be valuable in studying the effectiveness of drugs in people with cystic fibrosis. The creation of gut tissue that is almost a perfect copy has been successfully grafted into mice. This brings us closer to growing gut tissue transplants for individuals with inflammatory bowel disease, Crohn’s disease and chronic constipation. 
  •  The mini kidneys could be used to test drug candidates for toxicity as the kidney plays a key part in drug metabolism and excretion.
  • There have been many lives lost to liver failure due to the lack of donor organs available. Adult liver cells are difficult to grow but Takanori Takebe created “liver buds”, structures that resemble the liver of a six-week-old human embryo. These buds are far from an entire liver but Takebe hopes to infuse many thousands of buds into a failing liver in hopes of rescuing enough of its functions to make a transplant avoidable.

These “organoids” are better suited for developmental modeling and screening medicine than regular cells due to their 3D structure. The 3D structure and organization of tissues are important in understanding how they develop, how they become diseased, and most importantly, how they react to new treatments.

We may not be able to grow a whole replacement organ today but iPS cells are proving to be useful in other ways to combat diseases and neurological diseases.

Techstars Wrap-up: A Letter from Alex

Winnie Leung, Alex Jiao and Uly Rivera

Winnie Leung, Alex Jiao and Uly Rivera

12 weeks ago, we started the Techstars Seattle program. Last Wednesday, it culminated in our Demo Night, where we took the stage with one of our early customers and shared our vision of personalized medicine with the world. The program was a rigorous and intense 12 weeks – and the final month was as stressful as prepping for my PhD dissertation, but in the end I’m proud of all that we accomplished in the program. To those of you wondering what our experience was like, read on.

Many of the first weeks of the program were very structured. We spent a week refining our initial pitch and idea, as well as identifying key metrics to optimize for our business. We then spent a week meeting dozens of mentors in the Seattle area, some of whom have been integral for our business development, marketing, messaging, and introductions to other intelligent and motivated people. I truly believe that the main value of many accelerator programs is the network – the people I met, and the people they subsequently introduced me to – have helped both myself and the business grow in ways impossible without Techstars. The following weeks, we met with Techstars strategic partners and then focused on building our business.

Through these meetings, we began to explore collaborations and opportunities to build and develop technology in addition to offering our cell preservation service. These opportunities are very promising and we’re planning our next steps – I wish I could say more but these discussions and plans are still under wraps. Our mission has always been to not only preserve our customers’ cells for future use, but to push the field forward and accelerate the development of technology that can use our own cells. To this end, we’re now also focused on being an active player in this space.

Since Techstars started, we’ve refined our protocols, implement a full Quality Assurance program, and register with the FDA to ensure oversight on our processes and infrastructures. We’ve completely redone our website and have (hopefully) streamlined the user experience. We’ve also begun discussions with partners, such as major healthcare providers and research institutions in Washington, to begin to expand services and develop new technology. We’re looking to expand our reach to additional Bloodworks Northwest locations soon - we’re working hard to deliver on our promise of affordable and accessible cell preservation for all.

After Techstars, we’re starting to raise additional investments for expansion and we will continue to deliver our cell preservation service as we move ahead on certain collaborations. I hope you’ve enjoyed the journey with us and you’ll stay updated throughout. If you believe in our vision of the future, please talk to your friends and family about what we’re doing – and there’s a huge discount on our lifetime service that you can talk to Uly about if anyone’s interested.

Thank you so much for believing in us.

All the best,

Alex

CRISPR: A Primer

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CRISPR/Cas9 Genome Editing for iPSCs

                  Stem cell technology is an area of intense research in biotech as a research tool to study development and disease, but also for the potential therapeutic use of stem cells in repairing damaged tissue and curing disease (“Stem cells: a primer”). Pluripotent stem cells have the ability to divide indefinitely and to turn into any cell type in the body. An important discovery was made just 11 years ago – adult differentiated cells could be reverted or “reprogrammed” into pluripotent stem cells. These induced pluripotent stem cells or “iPSCs” are currently being studied in the lab. In order to be able to fully understand these cells and use them to study and treat disease, we need to be able to make specific changes to their genetic code. For example, we might want to fix a mutated gene that causes disease (such as the mutation which causes the blood disorder beta thalassemia) or we might want to knock out a gene that is causing problems (such as the gene for a receptor that allows HIV to enter a white blood cell).

Gene Editing Before Cut/Copy/Paste

                  Since the 1970s, scientists have been developing tools to make changes to genes. These tools have improved over time but were still limited their ability to make specific changes accurately without side effects. Two of the most powerful of these tools are zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). ZFNs and TALENs have a nuclease, which cuts the DNA strand, and a binding site to help guide the nuclease to the desired location on the genome. However, both of these tools have to be custom-made for each location, which is costly and time-consuming.

Self-Defense for Bacteria

The CRISPR/Cas9 system was originally discovered in bacteria, where it acts as a kind of immune system or self-defense. First, a virus infects a bacterium and introduces its DNA. This DNA is chopped up into pieces which are integrated into the CRISPR site in the bacterium’s DNA (Acquisition). If the same virus tries to infect the bacterium (or one of its descendants) again, the CRISPR DNA is transcribed into crRNA (crRNA Biogenesis). This crRNA combines with a second piece of RNA (tracrRNA) and the enzyzme Cas9, which is responsible for cutting the viral DNA. Since the crRNA matches part of the viral DNA, the crRNA/tracrRNA/Cas9 structure can bind to and cut the viral DNA (Interference). This system is not only specific because of the crRNA, but also simple because the Cas9 enzyme can be combined with any sequence of crRNA to match different genes for cutting.

CRISPR/Cas9 Mechanism. Credit: New England BioLabs Inc.

Room for Improvement

                  CRISPR/Cas9 has revolutionized the field of genome editing in only a few short years. However, scientists have already developed several methods for improving this technique. One of these was the combination of the crRNA with the tracrRNA into a single piece of RNA called the single guide RNA (sgRNA). This makes the system even simpler, going from three components (crRNA/tracrRNA/Cas9) to two (sgRNA/Cas9). Another improvement has been the use of “double-nicking” where two sgRNAs are used to bind to either side of a site on the genome. This allows us to cut out an entire gene and replace it with a new one. One last development has been the creation of a Cas9 nuclease which cannot cut DNA, but instead has added portions which can turn gene on or off. This has been used in the lab to help reprogram cells into iPSCs, but also to differentiate iPSCs into nerve cells.

 

Credit: New England BioLabs Inc.

The Future

The addition of CRISPR/Cas9 to our gene editing toolbox has the potential to greatly advance iPSC research. We already know of many diseases which are caused by one or two genes, and now we are better able to recreate the process of these diseases using genome editing of iPSCs. Developing cures for diseases using this technique is further down the road, but might be closer than expected. The first clinical trial of the CRISPR/Cas9 system in a human patient took place last year in China, and there is a great deal of hope for the future of this method.

Lungs Vital in Generating Blood Clotting Platelet Cells

Millions of people worldwide get affected by a condition called thrombocytopenia, a condition characterized by a deficiency of platelets, which functions in blood clotting. Thrombocytopenia causes substantial morbidity and mortality with prolonged bleeding and other health issues. Platelets are produced from big, mature bone marrow cells called megakaryocytes, and each can break up and release thousands of platelets [1]. It is widely believed that platelet production happens in the bone marrow. However, a recent paper by Lefrancais et. al. [2], found that the lung actually contributes to 50% of total platelet productions, and it holds populations of mature and immature megakaryocytes as well as a population of hematopoietic progenitors (stem cells that can turn into megakaryocytes and other blood cells). This has tremendous implications knowing that the lung plays a big role in production of blood cells and platelets.

In the study, different mouse lines were used to conduct the experiment. The first one is a reporter mouse line where the mice' megakaryocytes and platelets would glow green (from green fluorescence protein expression - which "reports" their cell identity and origin from fluorescence). The second mouse line is the control group, also known as the wild type - normal mice. Finally, the third line is the hematopoietic stem cell (HSC) deficient mouse line, where the mice are incapable of repopulating blood cell populations and also suffer from thrombocytopenia (lack of platelets).

With the reporter mouse line, they were able to image and visualize the number of platelets released into the  mouse lung circulation (Figure 1). They found that the lung is responsible for 50% of total platelet production and is a primary site for platelet generation.

Figure 1. Visualization of megakaryocytes and platelets production in the lung. Green indicates the megakaryocytes originating from the reporter mouse line, and red indicates capillaries. Arrows indicate where megakaryocytes are breaking up and undergoing platelet formation. [2].

Interestingly, apart from finding megakaryocytes within blood vessels in the lungs, the study also found megakaryocytes in the lungs outside of the blood vessels that are smaller than the ones in bone marrow and spleen and are less mature. In fact, 85% of the megakaryocytes are situated outside of the vessels and only 15% are within the vessels. To investigate the function of these resident megakaryocytes, they performed a single-lung transplant of the reporter mouse line into the HSC-deficient mouse line that are thrombocytopenic, and they flushed out the megakaryocytes that are in the blood vessels to make sure only resident cells remain - so they can attribute all observed effects to the resident megakaryocytes outside of the blood vessels. It was found that these HSC-deficient, thrombocytopenic mice were able to fully reconstitute platelet counts, which suggested that the implanted lungs had a population of more stem-like progenitor cells that can turn and mature into megakaryocytes. Finally, it was also shown that the lung transplant was able to reverse the condition of having a deficiency in HSCs in the HSC-deficient mice, as the megakaryocytes from the transplanted lung could actually migrate to the bone marrow to reverse HSC defects and associated deficiencies in a subset of blood progenitor cell population.

The results from this study give direct evidence that the lung plays a big role in platelet generation, and it can improve the approach in treating thrombocytopenia. Lung is an essential site where megakaryocytes produce and release mature platelets. The lung is also a residence site for megakaryocytes and hematopoietic progenitor cells, suggesting that it has untapped potential in the generation of blood cells and platelets.

[1] Patel, S. R., Hartwig, J. H., & Italiano, J. E. (2005). The biogenesis of platelets from megakaryocyte proplatelets. The Journal of clinical investigation, 115(12), 3348-3354.

[2] Lefrançais, E., Ortiz-Muñoz, G., Caudrillier, A., Mallavia, B., Liu, F., Sayah, D. M., ... & Krummel, M. F. (2017). The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature.

A Foray into Science: The Reality of Current Stem Cell Treatments

Part of my role with Silene Biotech is to oversee all communications regarding our company, cell preservation service, and the current state of the stem cell field. I update the Silene community on all major developments in the stem cell field, both bad and good. Below, I’ll discuss two cases that reflect both the unfortunate and promising sides of current stem cell therapies.   

First, we begin with the fact that there are no proven stem cell therapies to date. There are promising clinical trials addressing a variety of ailments and diseases that are going through the rigorous scientific process. Today, clinics that promise cures provide procedures that involve reintroducing stem cells derived from fat or bone marrow. The effects of these procedures vary and are unpredictable. Some people, including professional athletes, may swear by them but they remain unproven.

These clinics are also unregulated and promise unsubstantiated claims. The latest unfortunate case took place at a for-profit clinic in Florida. Three elderly women became blinded due to receiving an unproven stem cell treatment. These women, in their 70s and 80s, received cells that were injected into their eyes. The cells, derived from fat tissue, were advertised to combat their macular degeneration, the most common cause of blindness among the elderly. One woman became completely blind while the other two were effectively blind.

The other story I’d like to share is of a successful regulated clinical trial. In 2014 in Japan, a woman in her 70’s successfully halted her age induced macular degeneration after receiving a retinal transplant. This was part of a clinical trial that took the patient’s skin cells and turned them into induced pluripotent stem (iPS) cells. The iPS cells were then reprogrammed into retinal pigment epithelium (RPE) cells, the cells destroyed by macular degeneration. This procedure was the first involving the use of iPS cells to treat a patient’s condition.

After the procedure, the scientists from the Riken Institute monitored and analyzed the patient to ensure the procedure was successful. After two years of monitoring, they shared the positive results and that no negative effects occurred. The Riken institute is continuing their research and moving on with other clinical trials.

I share these stories because it is important to differentiate unregulated stem cell clinics from legitimate clinical trials. There’s a lot of false information and promises in the consumer stem cell industry today. And rather than turn a blind eye to these cases, it’s important to learn from these cases. There are promising trials, with new groundbreaking results every day. We monitor these trials to share any developments with you. As we continue to grow and expand our services beyond cell preservation, we look to partner with organizations that match our high standards of practice. The future of medicine is personalized treatment and we will help you utilize that future.  

How Aging Affects Function and Metabolism of Blood Stem Cells

With aging, tissues in the body deteriorate - we all know that. However, what does that mean on a cellular level? Let's look into how physiological aging affect the blood system - an integral part to every organ and tissue in the body - from a recently published Nature journal article titled  "Autophagy maintains the metabolism and function of young and old stem cells."

To give some background to the article, the blood system is comprised of many different blood cell types (like white blood cells, red blood cells, etc.), and they are all regenerated from hematopoietic stem cells (HSCs) (Figure 1). This makes them very critical for the proper maintenance and balance of the blood system. HSCs are rare in adults and are kept in low metabolic, quiescent (or dormant) state; in other words, they’re in hibernation state until they are called upon as needed to regenerate the blood system. Interestingly, the proper development of the blood system is also dependent on a process called autophagy. Autophagy can be thought of as the cell’s housekeeping system that keeps the cell clean for proper functioning; in more scientific terms, it is an intracellular degradation system that regulates the quantity and quality of organelles (functional units within a cell, can be thought of as a cell's internal organs) and macromolecules. With age, autophagy declines in many tissues, and this article is motivated in identifying how autophagy controls and affects HSCs’ function and aging.

Figure 1. Hematopoietic Stem Cell Differentiation. [Source]

For scientists, in order to study the function of something, one of the best ways is to take that out of the system and see what is affected. Similarly, to study the effect of autophagy, the study knocked out (or inactivated) the gene responsible for autophagy (the Atg12 gene) in adult HSCs in mice. The mice remained largely healthy, but had a skewed ratio of myeloid versus lymphoid cells in the blood, which resembled the myeloid-biased differentiation observed in old mice. HSCs with inactivated autophagy also had defective self-renewal activity resembling the functional impairment of old HSCs. From this, we can tell autophagy plays a role in maintaining the proper myeloid-lymphoid differentiation ratio as well as proper self-renewal activity.

Next, the effects of autophagy on the metabolism of HSCs were investigated. In terms of cellular metabolism, the mitochondria is likely the most important organelle that functions as the powerhouse of the cell, taking in nutrients and converting them to energy-rich molecules for the cell (Figure 2). HSCs deficient in autophagy were similar to old HSCs; their mitochondria powerhouses are more metabolically active as compared to those in young HSCs (demonstrated by increased cell size, increased oxygen consumption rates, and increased glucose uptake). These autophagy-deficient HSCs were also losing their quiescence and stemness (with accelerated differentiation into the myeloid lineage), which again resembled the deregulations characterized in old HSCs. Therefore, autophagy is essential for clearing metabolically activated mitochondria to allow HSCs to maintain in a more stem-like state.

Figure 2. Mitochondrion of a eukaryotic cell. [Source]

Finally, the study found that even though most blood cells showed a decline in autophagy with age, approximately one-third of old HSCs actually have increased autophagy levels, and these autophagy-activated old HSCs are the ones responsible for most of the blood repopulation. On the other hand, the autophagy-inactivated old HSCs are responsible for driving most of the blood aging phenotypes. However at this moment, it is unclear why some old HSCs have activated autophagy and others do not, but we do know that the level of autophagy activity is a determining factor on whether the HSC will be more young-like (being more regenerative) or old-like.

In summary, this paper demonstrated that autophagy is an essential process to remove activated mitochondria and controlling oxidative metabolism. These in turn are responsible for determining which genes get turned on/off (by changing external genetic patterns, also known as epigenetic modifications) for maintaining HSC stemness and regenerative potential. Thus, this study has identified a very specific cellular characteristic (you guessed it - autophagy) that can be directly targeted for improving old HSC function in preserving the health of an aging blood system. With further studies to better understand cellular aging, these findings would have large implications for rejuvenation therapies.

Your Heart Doesn’t Get Cancer — But That’s Why It Fails

The heart is a really fascinating organ. Functionally, it’s pretty simple — a mechanical pump responsible for pushing blood around your body. But this simplistic pump is also responsible for keeping us alive, and when our heart fails, we die. In fact, heart disease is, and has remained, the number one cause of death in the US since the 1930s, and heart attacks kill over 500,000 people a year in the US. However, when considering the total scope of heart disease and how it affects us, you never hear the term “heart cancer”. Ever wonder why your heart doesn’t get cancer? If so, read on!

The link between organ damage and repair

Broadly, if tissues or cells in your body are damaged, they need to be replaced. If you read my previous post, “Stem cells: a primer”, you’ll recall that usually a stem cell or progenitor population is responsible for replacing this dysfunctional or damaged tissue. Different organ systems and tissues have specific stem cells then which are responsible for this repair. For instance, your digestive system cells only live between 2–7 days before being replenished by a progenitor or stem cell population. For your digestive system, these cells are exposed to a harsh environment, like stomach acids and enzymes, that necessitates a constant replenishment of the cells as they become damaged quickly. Similarly, your white blood cells turn over relatively quickly as they patrol your body and fight off infections and are similarly replenished by progenitor cells. It’s reasonable to assume then, that regeneration is linked to the frequency of damage a tissue receives; cells that are constantly exposed to harsh, damaging environments tend to die quickly and need to be replenished. So tissues and organs that are more likely to be damaged generally have pretty active stem cell populations.

A link between regeneration and cancer

I’m not a cancer scientist (I’ll look to expand upon this with a more qualified scientist later) but in general, there is thought to be a link to a tissue’s ability to regenerate and also ability to form cancers or tumors. Each time a cell divides, it splits into two cells. Since there are two cells, a cell needs to copy its DNA. And our genome is pretty massive; we have roughly 3 billion base pairs, which are the information-storing portion of DNA. While our cells have incredibly good error-checking mechanisms to prevent mutations while copying DNA, even an incredibly high accuracy would still lead to an accumulation of mutations just due to the sheer number of cells and cell divisions through the course of our life. Putting that into numbers, our DNA “spellcheck” accuracy is thought to be around ~1/10¹⁰ mutations per base pair per cell division. With 6x10⁹ base pairs (twice the 3 billion, because our DNA is double stranded), that means a normal cell division would not even likely have a mutation, however after two divisions, a mutation would have likely occurred. We have ~37 trillion cells in our body, and some of them divide quite actively so you can imagine mutations do become a problem. There’s a lot of failsafes our bodies have to fight against cancer, but in general, the more a cell divides, the more likely it is to accumulate a mutation, and mutations in specific genes are thought to be the driving force of cancers. So, in general, the more a cell or tissue divides, the greater risk it has of developing cancer.

Does the heart regenerate itself?

So we’ve established that cells and tissues in harsher environments need to replenish themselves. But, conversely, when cells and tissues divide more, that makes them more susceptible to cancer. So what about the heart? Well, the heart, relatively speaking, is not exposed to much more than blood. Blood can carry viruses and bacteria, and exposure to these can actually lead to a heart infection, but this is relatively rare. So for the most part, our hearts are pumping away nonstop, safe deep in our bodies away from enzymes, acids, toxins, and environmental damage like UV rays. Instead of actively dividing, the heart focuses on actively pumping, and regeneration or division of the heart cells is incredible limited. The heart does get exposed to damage from the contraction process, so a little bit of cell replenishment is necessary, but how little is astonishing: a really cool study actually determined that only 50% of our heart cells are ever replaced over the course of our entire lives, meaning that you’re born already with half the heart cells you’ll die with. As a result, heart cancer or tumors from heart cells is incredible rare to the point where there has yet to be a confirmed case of heart cancer arising from heart cells; instead, the only tumors and cancers found the heart (still incredible rare) are from the supporting cells in the heart, or cancers from other parts of the body that have spread to the heart.

Your heart’s lack of regeneration causes it to fail

But as a result, the heart also lacks the ability to repair itself sufficiently after a more serious injury. Again, in general, the heart is not exposed to very much damage or trauma in daily life, so this is usually a non-issue. However, over time, a lot of this damage can accumulate and cause a myriad of problems to your heart. Some issues include high blood pressure and thickening of your heart muscle, “fibrosis” or scarring of your heart tissue just due to normal wear and tear, and “ischemia” or reduction of blood flow due to arteries narrowing/closing up due to cholesterol plaque accumulation. If the heart loses blood supply, since it’s so working so hard and requires tons of oxygen and nutrients it dies quickly. A well-known example of this is a “myocardial infarction”, or heart attack — this happens when an artery supplying blood to the heart becomes blocked and the blood supply to a portion of the heart stops or is dramatically reduced. This, in turn, causes massive cell death in the areas of the heart affected. And since the heart does not have great regenerative capabilities, when we have heart attacks, our hearts are not able to repair themselves adequately — which causes a number of downstream complications even if we survive the initial heart attack, like electrical problems and reduction of contractile function.

Summary

There’s a complex system of regeneration in your body. For tissues and cells that are damaged constantly, it makes sense to replenish the tissues and regenerate those cells more quickly. But for other systems, like your heart, it is more important to maintain constant pumping function since it’s so critical to survival. So for these systems, the regeneration is incredibly limited; only 50% of your heart cells are ever replaced. The upside? No heart cancer. The downside? No physiological repair for serious heart damage.

A Foray Into Science: A New Hope for Conservation

My name is Uly Rivera and I have the pleasure to work with individuals who have preserved their cells with us. Before I continue, I must disclose that I am NOT a scientist. In fact, I am the lone team member of Silene Biotech that isn't a doctor or a scientist. The lone muggle on a team full of science wizards, I stand alone with my Bachelor of Arts degree. 

But I am interested in the field of science. I am interested in studies and research that have far reaching implications on our daily lives and our future. I also love to connect with people and share information that I find vital, fascinating or entertaining. That said, I’d like to share some of the intriguing research, studies, and breakthroughs in the scientific world with you. They might relate to stem cells, personalized medicine or just some cool science stuff. And today we begin with a natural starting point from an online marketer - a cat related post. 
 
On March 1, 2017, the Smithsonian’s National Zoo and Conservation Biology Institute and Nashville Zoo announced the birth of a male clouded leopard. What makes this birth noteworthy besides the fact that a clouded leopard cub is beyond adorable? The birth was the result of an artificial insemination (AI) procedure using frozen/thawed semen. This is a first for this endangered species with big implications for conservation efforts.
 
The clouded leopard is a vulnerable species meaning that their population is decreasing. This is due to habitat loss and poaching, with exact numbers of the population unknown. Even with a breeding program in place by the Clouded Leopard Consortium, clouded leopard are difficult to breed in captivity and captive population is not self-sustaining. 
 
“This cub, the first clouded leopard offspring produced with cryopreserved semen, is a symbol of how zoos and scientists can come together to make positive change for animals and preserving global biodiversity,” said Adrienne Crosier, biologist at the Smithsonian Conservation Biology Institute.
 
“It means we can collect and preserve semen from clouded leopard populations around the globe and improve pregnancy outcomes from AI procedures in this species,” said Dr. Heather Robertson, Director of Veterinary Services at the Zoo.
 
This also represents an exciting possibility for other species that face extinction. And beyond the use of frozen/thawed semen in AI, there is the possibility of using induced pluripotent stem (iPS) cells to augment the breeding populations.
 
There is partnership between Japanese scientist and German researchers trying to save the nearly extinct northern white rhinoceros by producing eggs from iPS cells. With only three animals alive in a nature preserve in Kenya, the team is looking to produce eggs which would then be fertilized in vitro with frozen semen. The fertilized egg would then be carried to term by a closely related animal, possibly a south white rhinoceros.  

Conservation efforts in the wild are necessary for endangered species but using new scientific advancements could be a vital resource in the mission to save these species.
 
As for the unnamed clouded leopard cub, he will stay at the Nashville Zoo where he’ll be hand-raised to ensure survival and well-being. Plans are in place to eventually introduce him to a potential mate.

Tumor Prevention in Spinal Cord Stem Cell Treatment

Induced pluripotent stem cells (iPSCs) have great potentials in regenerative medicine in their ability to self-renew and be differentiated or grown into different cell types. One of these applications is to improve motor functions post spinal cord injury. However, because undifferentiated cells' and neural stem/progenitor cells' inherent nature to keep multiplying , one of the biggest challenges in their clinical application is to reduce their tumorigenicity - the ability of these cells to give rise to benign or malignant tumors. Interestingly, a recent article published in Stem Cell Reports titled "Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives" explored the efficacy of a suicide gene (a gene causing the cells to die naturally) introduced into iPSCs to prevent post-transplantation tumor formation in mice.

 

For a brief background, this group integrated the suicide gene called iCaspase9 (iC9) into two human iPSC lines that have previously shown to produce tumors. A small molecule called CID was also used as an inducer/activator for cell suicide. The iCaspase 9 system and CID were then tested in their ability to induce cell death both in cell culture studies and using mouse models.

To show the efficacy of the iCaspase 9 system, Figure 1 showed that with the integration of the suicide iC9 gene and the administration of CID, cell suicide is effectively achieved in the targeted cell lines.

 

Figure 1. Itakura, G., et. al. (2017). Stem Cell Reports.

This is consistent with the results in Figure 2 when the cell lines were transplanted into the injured spinal cords of mice, where they multiply and proliferate until the administration of CID. Interestingly, the hind limb motor function of mice showed improvement after transplantation, but declines after 2-3 weeks post transplantation due to the enlargement of tumor. However, functional recovery was significantly increased after treatment with CID with ablation of the tumor.

 

Figure 2.  Itakura, G., et. al. (2017). Stem Cell Reports.

Stained sections of the spinal cord in Figure 3 and 4 also showed that the transplanted neural stem/progenitor cells formed neural tumors, and these tumors can be ablated upon the activation of the iCaspase 9 system with CID.

 

Figure 3.  Itakura, G., et. al. (2017). Stem Cell Reports.

 

Figure 4.  Itakura, G., et. al. (2017). Stem Cell Reports.


In summary, results from this paper showed that the iCaspase 9 system with the suicide small molecule activator CID is effective in both cell culture studies and in mouse models. Injected CID can also cross the blood-brain-barrier to reach transplanted cells to do its works and ablate tumors in the spinal cord. This makes it an effective system to solve the problem of potential tumor formation in transplanted neural stem/ progenitor cells in the treatment of spinal cord injury. However, the lentiviral vector used to integrate the iC9 gene causes it not suitable for clinical application, as it integrates the gene into the genome. Thus, finding a non-integrating vector would be the next step and can bring the iCaspase 9 system closer to its clinical application.

Stem Cells: A Primer

Many of the questions I receive after a pitch or talking to prospective customers revolve around the ubiquitous but somewhat mysterious “stem cell”. Even though I was a bioengineer and not a developmental biologist, stem cell biology is actually one of my favorite areas of scientific study, and the advent of stem cell technology in the late 90s and early 00s was one of the motivating factors for me to go into Biomedical Engineering as an undergrad and into my PhD studies. Nearly 20 years after the first human embryonic stem cell lines were isolated by Dr. James Thomson, we’ve made incredible progress in the stem cell field. Unfortunately, us scientists aren’t usually great at disseminating this information widely and in an easy to understand format. In this primer, I’ll try to hit the main points of stem cell biology without going too deep into the weeds — I’ll remain as technically accurate (maybe with disclaimers) as possible but may generalize. If you’re a stem cell scientist or just an enthusiast and find issues with my generalizations — please comment! Otherwise, read on for a stem cell primer.

What are stem cells and what do they do?

The basics of stem cell biology start with the definition of what a stem cell is. Broadly, a stem cell is a cell that has two important functions: 1) self-renewal and 2) differentiation, or turning into another cell. Self-renewal means that the cell is able to divide (mitosis) and proliferate, or increase in number. Differentiation is the process by which a stem cell turns into another, more specialized cell. An example of this would be a hematopoeitic stem cell, or blood stem cell that resides in the bone marrow, dividing to increase its numbers (self-renewal), then differentiating into white blood cells for an immune response (author’s caveat: I know the technical lineage is through a progenitor population and then into a terminally differentiated cell).

Since stem cells can both self-renew as well as turn into other cell types, they’re often the mechanism by which tissues and organs can repair or replenish themselves. Many tissues have resident stem cell populations, usually referred to as “adult stem cells”, that are responsible for downstream repair or replenishment of damaged or old tissues. Why is this necessary? Most cells in the body (somatic cells, or basically specialized, differentiated cells, or basically non-stem cells) have limited self-renewal capabilities. After a number of cell divisions, our cells will become “senescent”, or stop dividing (due to shortening of their telomeres) (read more about senescence in the appendix). Other times, our cells will undergo “apoptosis”, or programmed cell death (or necrosis, which is a more traumatic form of cell death). Either way, a cell population will need to be replaced, either due to the lack of cell function (senescence) or death of the cell (apoptosis, necrosis), which is where stem cells come in. They’ll divide and differentiate and replace lost cells. Our bodies are very yin and yang, and a lot of biology is a balance.

So take home message: stem cells are cells that self-renew and differentiate into specialized cells (like skin cells, muscle cells, blood cells). Most tissues have resident stem cells to replace lost, damaged, or aged tissues, but these are typically referred to as “adult stem cells”.

Not all stem cells are equal

Now that we’ve defined what stem cells are and their function, another important concept is that not all stem cells are equal. Stem cells, broadly, can be grouped into different levels of “potency”, or differentiation potential. This concept was modeled beautiful by CH Waddington and Waddington’s Hill. Imagine stem cell potency like a marble at the top of a hill, with the marble representing the cell and the hill representing different levels of potency. If you’re a physics nerd, you can relate this fuzzily to potential energy.

 

Waddington’s Hill. Waddington, C. H. (1956). Principles of Embryology

At the top of the hill, our cells are the least differentiated and have the most potency, or the ability to turn into the most cell types. This level of potency — the ability to differentiate into all 3 germ layers and extra-embryonic (placental) tissue — is called totipotent. An example of a totipotent cell is a zygote, or basically a fertilized egg cell. Once the cell begins to divide and differentiate, or starts to go down Waddington’s Hill, it loses potency — it cannot go back up the hill without outside intervention (think of this like a marble rolling down a hill — its not going to go back up that hill without an external force). The next level of potency is called pluripotent, or the ability to turn into all 3 germ layers (or basically, any cell or tissue in the adult body). An example of a pluripotent cell is an embryonic stem cell. As a pluripotent cell begins to differentiate and roll down Waddington’s Hill, the cell loses potency and becomes multipotent, or the ability to turn into more than one cell type, but not all 3 germ layers. An example of a multipotent stem cell is the aforementioned blood (hematopoeitic) stem cell, which can turn into all 5 types of white blood cells. Further down the hill, and more specialized, come progenitor cells, or oligopotent (although I don’t see this term used that much). Progenitor cells typically can only differentiate into a few cell types that are closely related — an example of this would be a lymphoid progenitor cell, which can only turn into lymphocytes (T cells, B cells, Natural killer cells), which is 1 of the types of white blood cells. Finally, some people believe in the existence of unipotent stem cells, which can self renew but are only able to turn into 1 cell type. An example of a unipotent cell would be a hepatoblast, or liver cell precursor, that can self renew but can only turn into a hepatocyte (this happens during development), but there is not much focus on unipotent stem cells (if they exist, again, I believe there’s debate around this).

So in summary
totipotent: stem cells that can turn into all 3 germ layers and placental tissue. Not found in the adult human body
pluripotent: stem cells that can turn into all 3 germ layers. Not found in the adult human body
multipotent: stem cells that can turn into multiple other cell types
progenitor/oligopotent: stem cells that can turn into a few, related cell types

The specific stem cell is important

Putting this together, stem cells are cells that self-renew and turn into other cells. Our bodies have stem cells that are able to replenish old or damaged tissues. However, not all stem cells are created equal — some stem cells have the ability to turn into more cell types than others. Now, thinking of the concept of Waddington’s Hill, since certain stem cells have lost potency because they have fallen down Waddington’s Hill (or differentiated into a more specialized cell type), they cannot replace lost or damaged tissue of cells that they cannot turn into. For instance, a blood stem cell (hematopoeitic) can turn into red and white blood cells, but cannot turn into heart cells, as they’re too far removed from the heart lineage. For researchers and scientists, looking at developmental biology and plotting out stem cell lineage charts or maps like this one, it’s relatively easy to determine which stem cell types can yield specific cells of interest. For instance, being a heart researcher, I know that hematopoietic, or blood, stem cells do not differentiate into heart cells. There is a bit of debate sometimes on whether or not certain multipotent stem cells can turn into specific cells — like a mesenchymal stem cell turning into a heart cell (my take: they can’t) — but as this field continues to develop, most of these pathways and potentials will be well mapped out.

 

Map of stem cell differentiation. Credit: philschatz.com

The importance of this? When reading studies or about interventions using stem cells, it’s important for me to look at A) the stem cell being used, and B) the tissue type being repaired. For instance, as we just noted above, blood stem cells do not turn into heart cells. Therefore, a study using blood stem cells injected into the heart after a heart attacked aimed at regenerating heart tissue raises some red flags to me. Since the blood stem cells cannot turn into heart cells, that means regeneration is unlikely to come from the injected stem cells. Instead, if there is any regeneration, it would have to come from the heart cells interacting with the blood stem cells (like the heart cells start dividing and growing) — but this would be extremely atypical of heart cells. So instead, it would make sense that if any improvements were seen with injecting blood stem cells into the heart after a heart attack, it would be temporary — it is unlikely that either the stem cells or the existing heart cells regenerated heart tissue. There’s even an additional level of complexity here — even if a stem cell can turn into a specific cell type, some cells are easier for the stem cell to turn into than others. For instance, mesenchymal stem cells can turn into muscle cells, but will more easily turn into fat or bone without additional manipulation, and we’re finding that simply putting the stem cell into the tissue of interest isn’t enough of a cue to turn them into that cell type. It usually takes a lot of external (in vitro) manipulation of stem cells to turn them into a cell of interest.

Take home message here: based on which stem cell we’re using, that can affect the cell types that the stem cell can differentiate into. Therefore, we (scientists and doctors) should plan well-reasoned studies using the appropriate stem cell for the appropriate tissue.

Reprogramming cells — induced pluripotency

One special stem cell worth mentioning is an induced Pluripotent Stem cell, or iPS cell. I’ll write more about this special cell type at a later date, but essentially in 2006, a Japanese medical scientist by the name of Shinya Yamanaka was able to reprogram a skin cell into a pluripotent stem cell. If you recall from the previous section, an example of a pluripotent stem cell is an embryonic stem cell, so essentially Dr. Yamanaka was able to reprogram a skin cell into an embryonic stem cell. If we refer back to the Waddington Hill analogy, this means basically that now we have the ability to take a cell that’s fallen to the bottom of Waddington’s Hill, and move it back near the top to an pluripotent state by reprogramming or manipulating the cell. As you can imagine, this opens up the door to a number of exciting possibilities — now any cell in our bodies can be reprogrammed to a pluripotent state. Since the reprogrammed iPS cells are pluripotent, they can then be turned into any other cell type in our body. So instead of injecting blood stem cells into the heart to repair damaged heart tissue (with little to no long-term effects as analyzed above), we can reprogram that blood stem cell into an iPS cell, turn those iPS cells into heart cells, and then inject those heart cells back into the heart to regenerate heart muscle. Of course, you could also do this with embryonic stem cells, and in fact, research from the University of Washington (and by a former professor of mine) has shown that injection of pluripotent stem cell-derived heart cells was able to successfully regenerate damaged monkey hearts. However, the ability to reprogram your own cells into iPS cells could lead to more personalized therapies, but this field is still very new.

Basically “new” technology allows us to reprogram cells back into a pluripotent, or embryonic-like state. But one advantage of this technology is now we can generate our own pluripotent stem cells, which otherwise do not exist in the adult human body.

Summary

Hopefully that clarifies a lot of the ambiguity of stem cells. Stem cells are an important innate part of repairing our bodies already but can also serve as an additional, powerful tool as a therapy. However, given how popular stem cell medicine is now, there is a lot of noise with certain doctors or scientists broadly using stem cells to treat every disease possible without a sound fundamental hypothesis. It’s still good to be cautiously optimistic about the field — we’re very early — but we must also be very discerning as to what studies are being done with which type of cells and why.

-Alex

Appendix

Some theorize that this process of cellular senescence evolved to reduce cancer risk — whenever cells divide, or through daily processes, a number of mutations accumulate in their DNA, which could possibly give rise to cancer. These senescent cells can be cleared by our immune system, but an accumulation of senescent cells is a hallmark of aging. Going back to that yin yang analogy, our bodies might be balancing between reducing cancer risk with losing cell and tissue function.

*Slight programming note about the existence of pluripotent stem cells in the adult body: I’m not really sure if it’s a change in the use of terminology, however some stem cells have been found in the adult human body which have been referred to as pluripotent in publications, e.g. intestinal crypt stem cells or dental pulp stem cells. Personally, I don’t think these cells are pluripotent and I don’t believe any of these studies have demonstrated true pluripotency of the cells — they may express certain pluripotent markers but I don’t believe we’ve seen definitive 3 germ layer lineage differentiation of these cells, like ES or iPS cells. Moreover, I think the publications that refer to these cells as pluripotent actually mean multipotent — again, maybe the definition of pluripotent has gotten more specific over the years.

Regenerating The Heart: Exciting New Developments

Heart disease is one of the most commonly-observed serious diseases in the United States, affecting over ten percent of the adult population to some degree. Heart disease essentially results from either an extreme deterioration or overgrowth of the muscular tissue of the heart that pumps blood throughout the body, and typically has grave implications for patients: over fifty percent die within five years of diagnosis.

 

Heart failure can be an extremely serious and debilitating ailment. Depending on the degree of failure, patients may experience conditions that at a physiological level cannot be effectively cured with drug therapy. Because it is also one of the most commonly-experienced health issues in middle-aged and elderly Americans, the demand for donor hearts considerably exceeds supply. Even in the event that a donor heart is available, after surgery, patients require immunosuppressive therapy for the rest of their lives to prevent the body from rejecting the donated organ. This, in turn, has driven the investigation of new therapies using stem cells to regenerate the heart.

Of these, one particularly promising apporach has recently been discovered at the Center for Cardiovascular Medicine at the University of Washington. Many earlier approaches to regenerating heart tissue involved regenerating heart muscle tissue either around a demuscularized skeleton of connective tissue from cadaver hearts, or regenerating small 'patches' of heart tissue outside the body to be surgically implanted in place of diseased tissue. But the latest and most successful attempt at regenating heart tissue at larger scale involves injecting large samples of undifferentiated stem cells directly into diseased areas of the heart.

This approach, which had been attempted previously with considerable success in mice and rats, was recently attempted in pigtail macaques, which are similar in size and build to rhesus monkeys, at the University of Washington. The monkeys had heart attacks induced, and then underwent injections of stem cells in areas of the heart where scar tissue had formed afterwards. In the treated monkeys, new heart muscle as wide as 3/5 of an inch formed successfully and was visually distinguishable with the naked eye - over ten times the size accomplished successfully by previous researchers. The grafts also successfully vascularized, growing not just muscle tissue but new blood vessels as well, drawing blood and therefore oxygen and nutrients to the new tissue, meaning that the tissue would likely continue to function successfully.

Previous attempts at the same technique in mice and rats, whose hearts can beat as fast as 400 beats per minute or more, had been considered completely successful as the heart's rhythm was not affected by the regenerated tissue. But in the macaques, whose heartbeat is considerably slower and, at an average of 115 beats per minute, much closer to that of humans' resting heart rate, the heartbeat became slightly irregular in the monkeys who received stem cell injections - which the researchers attributed to incomplete regrowth of the nerve tissue that would ordinarily regulate the heartbeat.

Future research, therefore, will likely focus on improving the regularity of the heartbeat in recipients of regenerated tissue. This may involve greater complexity of tissue regeneration in order to more completely regenerate the nerve tissue lost in the process of the patients' heart attacks; or it may involve combining stem cell injections with the use of a pacemaker and/or drugs that regulate the heartbeat so that patients experience fewer side effects of the resulting arrythmia. But in all cases, patients will, in the very near future, have access to a treatment for heart disease far superior to the options currently available.

The Silene Stenophylla: An Introduction

Over 32,000 years ago, a squirrel buried a small group of seeds near the Kolyma river in Siberia as part of a normal cache used to provide sustenance during the long, cold Siberian winters.

Unearthed from over 120 feet below the surface layer of permafrost, the seeds had been surrounded by bones from mammals now both living and extinct: bison, mammoth, and woolly rhinoceros. Although the many of the seeds had been damaged to a considerable degree, several contained recoverable material.

The Russian team to make the discovery were able to recover and successfully germinate several plants, which differ in both flower and leaf shape from modern variants of the Silene stenophylla plant. These recovered plants grew, flowered, and after a year were able to create seeds of their own - reproducing variants of their own type rather than of the modern variant.

For botanists, this was an important scientific discovery, as the previous title-holder of "oldest regenerated seed" was a date palm just 2,000 years old. This seed, however, had been preserved in a dry, cool area - not the water-rich permafrost environment in which the Silene stenophylla seeds were frozen, which is more comparable to the environment in which many modern 'seed vaults' store their contents - making the regeneration of the Silene stenophylla an important proof of concept for botanists worldwide.

For us, the Silene is not just an important scientific discovery, but also a signal of developments to come for all humanity: the introduction of an era of personalized, regenerative medicine using patients' own cells, ending the need for invasive transplants and their associated immunosuppressive therapy, which in many cases can cause side effects as debilitating as disease itself.

We look forward to working with you!

 

 

Silene Biotech: A Letter From Our Co-Founder

Thank you so much for your support and business. We hope that the process to preserve your cells has been straightforward, easy and exciting. We love meeting our customers and you motivate us to continue growing and improving every day.

I’m writing to you today to share some news: we’ve decided to change our name to better reflect the potential of the services we’re offering. As of today, we’re now Silene Biotech instead of miPS Labs. Nothing has changed with the storage or handling of your cells or your data.

Why Silene? It’s because of one of my favorite recent scientific discoveries. 32,000 years ago, a squirrel buried the seeds of a plant, the Silene stenophylla, in the Siberian permafrost. In 2012, scientists unearthed these preserved seeds and successfully germinated them, resulting in the growth of a mature, flowering plant. Our service mimics what this ancient squirrel did thousands of years ago – save cells for later, and we believe your cells will be the seeds of improved health in your future. If you have any thoughts on the new name, please let us know!

We hope that 2017 is treating you well and we’re excited to see how the field continues to develop.

Sincerely,

Alex

Cofounder & CEO

Silene Biotech (Techstars '17)

 

Regeneration of Bones & Bone Marrow

Among the therapies currently available that utilize tissue regeneration with induced pluripotent stem cells, those involved in regenerating bones and bone marrow are some of the furthest along in the development process as a result of their more simple nature.

 

In healthcare, bone fractures and breakages resulting from external trauma are relatively common occurrences. But there is often a point in aging at which the risk of bone breakage from everyday stresses increases. This is particularly the case in osteoporosis patients, whose bones fail to adequately rebuild themselves during the body's normal processes of bone breakdown and renewal. The result is that the bones of osteoporosis patients become increasingly porous and weak, increasing the likelihood of breakage or collapse - particularly in bones affecting everyday mobility: the hips, vertebrae, and wrists. Eventually, most if not all osteoporosis patients will suffer from some degree of spinal compression fractures, resulting in a hunched-over profile when upright.

In cases of more severe trauma, bones may be damaged to such a degree that permanent reinforcement materials or joint replacements may be deemed necessary. In these cases, induced pluripotent stem cells cultivated from the patient can be used to grow new bone tissue outside the body, which can be shaped to match the damaged bone and ultimately used to surgically implant and replace it. This approach allows patients to recover more quickly and reclaim a greater degree of mobility - without the need for the immunosuppressive drug therapy ordinarily required with bone grafts or donation, and without the need to use pins, screws, and other supports to continue attempting to repair an already-compromised bone.

 

Regeneration of patients' bone marrow using induced pluripotent stem cells is likewise becoming increasingly common. In cases of leukemia, where the option to use donated bone marrow to replace patients' own bone marrow is commonly utilized to permit higher doses of chemotherapy in order to more quickly and effectively eliminate cancer cells, the use of donated bone marrow first requires a search for a compatible donor; a transplantation process that is fairly arduous and painful for both donor and recipient; and follow-up treatment not only to manage chemotherapy but also to provide immunosuppressive assistance with the donated marrow.

Bone marrow regeneration from patients' own cells, known as an autologous bone marrow transplant, is often far preferable - eliminating the donor search and extraction processes entirely while eliminating the need for follow-up immunosuppressive therapy, thereby increasing the chance of remission and the potential for a faster recovery.

Tissue Regeneration in Lung Disease

Diseases of the lungs are some of the most common causes of illness and death worldwide, particularly in individuals over age 50. Most research in lung diseases with induced pluripotent stem cells thus far has focused on chronic obstructive pulmonary disease, or COPD. In the near future, induced pluripotent stem cells will likely be used for larger-scale tissue regeneration purposes in patients who have lost significant areas of their lungs to cancerous tumors, and in patients suffering from diseases of autoimmune inflammation, such as bronchiolitis.

Typically, COPD is the focal point of research and the target of the most advanced treatments in lung disease as it is the most likely form of lung disease to lead to major cancers. Although genetics do play some role in the development of COPD, it is primarily known as an obstructive lung disease, in which airflow is reduced substantially by regular exposure to toxic inhaled compounds: tobacco and other smoke, air pollution, and occupationally-related fumes from dusts to paint and other chemicals. Because the tissues of the lungs repair themselves at a relatively slow rate relative to other body tissues, the prolonged, repeated exposure to toxins that is characteristic in most cases of COPD is often impossible for the body to overcome by itself.

 

In COPD, gradual buildup of contaminants within the lungs, as well as an inflammatory response to those contaminants, causes a gradual breakdown of the connective tissue within the lungs, reducing their response to the expansions and contractions of the lungs that ultimately move air in and out of the body. This results in progressively worsening shortness of breath, reduced lung capacity, and increased vulnerability to infections and environmental irritants. 

At present, research on induced pluripotent stem cells (iPSCs) in lung disease has focused on increasing the lungs' natural rate of self-repair by introducing undifferentiated cells - i.e., cells that have not yet been transformed into lung tisue in the lab - into damaged areas of the lungs and using those cells to accelerate the healing of damaged tissues while removing the primary cause of exacerbation, generally cigarette smoke or chemical exposure. While this has shown to have some benefit, the greatest promise of regenerative medicine in lung disease likely lies in the cultivation of fully differentiated, new lung tissue to entirely replace diseased areas of the lung which, unlike transplanted tissue taken from human donors, will require no immunosuppressive therapy to maintain.

Color-Coded Stem Cells Offer New Possibilities in Research

The Allen Institute have created the first color-coded stem cells, opening a wide array of new possibilities in research. Researchers will now more easily be able to evaluate stem cell differentiation and to study the contrast between diseased cells and normal cells, thereby accelerating the development of personalized treatments for diseases. Read more here.

First Successful Lab-Grown, Innervated Gut Tissue

labgrowngut.jpg

A major advancement in tissue regeneration, the first sample of innervated intestinal tissue has been cultivated using induced pluripotent stem cells. This tissue contains nerve endings, which is the first step in enabling regenerated tissue to complete the muscular expansions and contractions known as peristalsis that permit the intestine to complete the physical component of digestion. Read more here.

What is in-vitro disease modeling? Revolutionizing treatment with induced pluripotent stem cells

When prescribing a course of treatment for a disease, physicians face many complex challenges. In many of the diseases addressed by induced pluripotent stem cell research, a physician using the most up to date approaches will generally first attempt to slow the progression of the disease, and reduce the impact of the symptoms the patient experiences with pharmaceutical interventions, i.e., by prescribing drugs.

 

In doing this, physicians are - despite years of training and experience - faced with an uncertain outcome that may delay conclusive results significantly, by months or even years. Finding the best combination of drugs, and dosages of those drugs, with which to treat each patient is generally a lengthy process of trial and error - with symptoms taking as long as several months to be reflected in a patient's day-to-day condition.

Induced pluripotent stem cells show incredible promise for expediting this process of determining the best course of action to treat a disease. From a simple blood draw, a representative sample of any tissue in a patient's body can be generated - from the neurons of Alzheimer's patients, to the pancreatic beta cells of diabetes type 1 sufferers.

 

Once cultivated in vitro, or outside the body, these induced pluripotent stem cells can cheaply, quickly, and easily be used to test and select the most effective combination and dosage of drugs for each patient's unique body chemistry and physiology. The effects of each potential drug, at a wide variety of doses, can be rigorously observed and measured at a cellular level - without waiting weeks or even months for physical symptoms to manifest themselves in patients' outwardly observable condition. This can, if used properly, shorten the treatment process by months or even years, slowing or even halting the progression of a disease.