Stem Cell Research

Dr. Michael West, Dr. Robert Lanza, Biotime Inc., Advanced Cell Technology, And International Stem Cell Corp.: Comments, As All Move Forward Toward A Stem Cell Therapy

Both Biotime Inc. (BTIM) and International Stem Cell Corp. (ISCO.OB) have licensed extensive patent rights from Advanced Cell Technology (ACTC.PK), all in the stem cell research and stem cell therapy arenas.  Both continue to move toward product development while adding intellectual property to that licensed from ACTC, making the combined intellectual property of the three entities easier to evaluate than that of the individual companies. 

Advanced Cell Technology, motivated by the need for operating capital, licensed most of its rather broad stem cell intellectual property -- mostly developed by Dr. Robert Lanza -- to ISCO and BTIM over a period of years.  Then, about a year ago, ACTC took the next step which was to find a joint venture partner, a South Korean Company. ACTC contributed its remaining intellectual property to the joint venture, all except that pertaining to stem cell research for eye diseases.  The company has recently filed an Investigational New Drug (IND) Application with the US Food and Drug Administration (FDA) to initiate a Phase I/II multicenter study using embryonic stem cell derived retinal cells to treat patients with Stargardt’s Macular Dystrophy.  Advanced Cell Technology's market capitalization is approximately $75 million.

Both Biotime and International Stem Cell follow a business model that calls for the sale of cell culture products to researchers in the stem cell research arena in order to promote the development of proprietary stem cell treatments.

Dr. Michael West, CEO of Biotime, is one of the early rock stars of stem cell research.  He has not only been around a long time (a founder of Geron and a former CEO of Advanced Cell Technology), he is one of a small group in the field that can increase the market value of his company -- if only momentarily -- by giving a speech at a conference.  He has managed to accomplish several things for Biotime this year.  These things have little to do with product development but have a lot to do with the business structure of Biotime as it sets itself up for the development of anticipated stem cell therapies.  This business structuring has also had a lot to do with the market capitalization of Biotime Inc., particularly the actuality and future possibility of raising capital directly in the subsidiaries.  Since September 30th of this year Biotime's market capitalization has increased by $30 million or roughly 30%.

This is what has increased Biotime's market capitalization:

Magnetism And Nanotubes May Be Means Of Directing Stem Cells To Specific Point Where Treatment Is Needed

In August, University College London researchers demonstrated a technique whereby endothelial progenitor cells – a type of stem cell shown to be important in vascular healing processes – were magnetically tagged with a tiny iron-containing clinical agent, then successfully targeted to a site of arterial injury using a magnet positioned outside the body.

The result was a five-fold increase in cells at a site of vascular injury in rats. The team also demonstrated a six-fold increase in cell capture in an in vitro flow system (where microscopic particles are suspended in a stream of fluid and examined to see how they behave).

Dr Mark Lythgoe, UCL Centre for Advanced Biomedical Imaging and lead researcher said, "Because the material we used in this method is already FDA approved we could see this technology being applied in human clinical trials within 3-5 years. It’s feasible that heart attacks and other vascular injuries could eventually be treated using regular injections of magnetized stem cells. The technology could be adapted to localize cells in other organs and provide a useful tool for the systemic injection of all manner of cell therapies. And it’s not just limited to cells – by focusing tagged antibodies or viruses using this method, cancerous tumors could be much more specifically targeted.”

Panagiotis Kyrtatos, also from the UCL Centre for Advanced Biomedical Imaging and lead researcher of the study, added: “This research tackles one of the most critical challenges in the biomedical sciences today: ensuring the effective delivery and retention of cellular therapies to specific targets within the body."

Now, Rice University and the Texas Heart Institute have received a two-year $1 million Challenge Grant to develop an advanced stem-cell-tracking technology based on an ultrasensitive class of magnetic resonance imaging (MRI) contrast agents invented at Rice in 2005.

The grant's purpose is the refinement of cell-tracking nanotube technology that could make magnetic resonance imaging (MRI) up to 40 times more sensitive than existing MRIs and help guide adult stem cells within the human body to repair damaged hearts.

Autologous Stem Cell Transplants Can Treat Heart Disease Study Finds

Out of the estimated 1 million people in the U.S. who suffer from chronic, severe angina — chest pain due to blocked arteries — about 300,000 cannot be helped by any traditional medical treatment such as angioplasty, bypass surgery or stents. This is called intractable or severe angina, the severity of which is designated by classes. This study included class 3 or 4 patients, meaning they had chest pain from normal to minimal activities, such as from brushing their teeth or even resting.

Consisting of 25 sites totalling 167 subjects, this Phase II study claims to be the largest national stem cell study for heart disease.   it also claims to be the first to show evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk.  We use the word 'claims' not to disparage in any way these results achieved by Feinberg School of Medicine at Northwestern University researchers. It is used simply because several other studies, perhaps smaller, have achieved similar positive results.

In this 12-month, double-blind trial, autologous (taken from the subject) purified stem cells (hematopoietic stem cells), referred to as CD34+ cells, were injected into the subjects' hearts in an effort to spur the growth of small blood vessels that constitute the microcirculation of the heart muscle. Researchers believe the loss of these blood vessels contributes to the pain of chronic, severe angina.

Unraveling The Mechanisms Behind Organ Regeneration

The search for the holy grail of regenerative medicine—the ability to "grow back" a perfect body part when one is lost to injury or disease—has been under way for years, yet the steps involved in this seemingly magic process are still poorly understood.

Some time ago we posted about Max Planck Institute research on Salamanders.  Salamanders regrow lost limbs and Elly Tanaka at Planck has been studying how they do so. Tanaka and colleagues found that salamander regeneration begins when a clump of cells called a blastema forms at the tip of a lost limb. From the blastema come skin, muscle, bone, blood vessels and neurons, ultimately growing into a limb virtually identical to the old one.

But here's the surprise: Rather than having their cellular clocks fully reset and reverting to an embryonic state, cells in the salamanders’ stumps became slightly less mature versions of the cells they’d been before.  In other words they don't revert to pluripotency.

Now researchers at the Salk Institute for Biological Studies have identified an essential cellular pathway in zebrafish that paves the way for limb regeneration by unlocking gene expression patterns last seen during embryonic development. They found that a process known as histone demethylation switches cells at the amputation site from an inactive to an active state, which turns on the genes required to build a copy of the lost limb.

Salk Institute researchers, lead by Juan Carlos Izpisúa Belmonte Ph.D, used zebrafish, a small fish from the minnow family, to study limb regeneration. "If you amputate the tail of the zebrafish, it regenerates in about a week, seemingly with no effort and leaving no scar," explains Scott Stewart Ph.D. "What's more, it regenerates a perfect copy and—like growing grass—it will do this over and over again." In other words, the zebrafish has the same regenerative capacity as the salamander.

Johns Hopkins and Harvard Add To Previous 2009 Findings On Differnces Between Induced Pluripotent And Embryonic Stem Cells

In July 2009, UCLA and Broad Institute researchers analyzed induced pluripotent stem cell lines derived with newer methods that didn't require integration of the reprogramming factors. Their analysis showed different molecular signatures between iPS cells and their embryo-derived counterparts, and these signatures showed a significant degree of overlap with those generated with integrative methods.

"We can’t explain this, but it appears something is different about iPS cells and embryonic stem cells,” said Bill Lowry, a researcher with the Broad Stem Cell Research Center. “The differences are there, no matter whose lab the cells come from, whether they’re human or mouse cells or the method used to derive the iPS cells. Perhaps most importantly, many of these differences are shared amongst lines made in various ways.”

Then in September came work regarding the differences between induced and embryonic stem cells done by UCSD and the Salk Institute. 

By creating iPSCs from human neural stem cells without the use of viruses, UCSD and Salk scientists learned something that moved toward an explaination of some of the questions raised by the UCLA/Broad Institute results. What they found was this: While the genetic transcriptional profile of the new iPSCs was closer to that of embryonic stem cells than to human neural stem cells, the iPSCs still carried a transcriptional "signature" of the original neural cell.

"While most of the original genetic memory was erased when the cells were reprogrammed, some was retained," said lead researcher Alysson R. Muotri, UCSD Stem Cell Program researcher who added that in the past it wasn't known if this retinue was caused by the use of viral vectors.

Although genetically identical to the mature body cells from which they are derived, induced pluripotent stem cells (iPSCs) are notably special in their ability to self-renew and differentiate into all kinds of cells. Now researchers from Johns Hopkins and Harvard have detected a remarkable if subtle molecular disparity between the two: Turns out they have distinct "epigenetic" signatures; that is, they differ in what gets copied when the cell divides, even though these differences aren't part of the DNA sequence.

Gladstone And Stanford To Develop Induced Pluripotent Stem (IPS) Cells For Cardiac Stem Cell Treatments

Researchers from the Gladstone Institute of Cardiovascular Disease (GICD), led by Director Deepak Srivastava, MD, will collaborate with a Stanford research team led by Robert Robbins, MD, professor and chair of cardiothoracic surgery, to investigate the use of induced pluripotent stem cells (iPS cells) to repair damaged heart muscle. The research consortium will be funded by the National Heart, Lung and Blood Institute (NHLBI).

iPS cells result from the “reprogramming” of adult cells into cells closely resembling embryonic stem cells. Like ESCs, they can develop into any cell type in the body. This technology was developed by Gladstone investigator Shinya Yamanaka, MD, PhD. the 2009 Lasker Award Recipient for Biomedical Research.

"Important gaps remain in our understanding of stem and progenitor cells," said NHLBI director Elizabeth Nabel, MD. "This consortium holds great promise to expand our knowledge and uncover therapeutic applications of great public impact.”

Neural Stem Cells In Mice Affected By Gene Associated With Longevity

A gene associated with longevity in roundworms and humans has been shown to affect the function of stem cells that generate new neurons in the adult brain.  The study suggests the gene may play an important role in maintaining cognitive function during aging.

Unlike skin or intestine, the adult human brain doesn’t make a lot of new cells. But those it does are critical to learning, memory and spatial awareness. To meet these demands, the brain maintains two small caches of neural stem cells. In each cache, stem cells can self-renew and give rise to neurons and other cells known as oligodendrocytes and astrocytes. Properly balancing these functions allows the generation of new nerve cells as needed while also maintaining a robust neural stem cell pool.

“It’s intriguing to think that genes that regulate life span in invertebrates may have evolved to control stem cell pools in mammals,” said Anne Brunet, PhD, assistant professor of genetics at the Stanford University School of Medicine.

As mice and other organisms age, the pool of neural stem cells in the brain shrinks and fewer new neurons are generated. These natural changes correlate with the gradual loss of cognitive ability and sensory functions that occur as we approach the end of our lives. However, the life span of some laboratory animals can be artificially extended by mutating genes involved in metabolism, and some humans outlive their life expectancy (about 70 years for someone born in 1960) by decades. Brunet and her colleagues wanted to know why.

Small Molecule Platform For Commercial-Scale Reprogramming Announced

Fate Therapeutics, Inc. claims to have significantly improved the speed and efficiency of reprogramming adult cells into human induced-pluripotent stem cells (iPSCs) using a combination of small molecules.

The discovery, which was made by Sheng Ding, Ph.D. under a research collaboration between Fate Therapeutics and The Scripps Research Institute (TSRI), represents a more than 200-fold improvement in reprogramming efficiency and reduces the reprogramming period to two weeks as compared to methods using only the four reprogramming factors (Oct 3/4, Sox2, Klf4 and c-Myc).

This advancement has implications for the creation of "pharmaceutical grade" iPSCs, reprogrammed cells that can be produced without genetic modification at commercial scale quantity, quality and consistency.