Using Human Stem Cells to Predict the Efficacy of Alzheimer’s Drugs

Scientists who work in the pharmaceutical industry have seen this time and time again: A candidate drug that works brilliantly in laboratory animals fails to work in human trials. So what’s up with this?

Now a research consortium from the University of Bonn and the biomedical company Life & Brain GmbH has shown that animal models of Alzheimer’s disease fail to recapitulate the results observed with cultured human nerve cells made from stem cells. Thus, they conclude that candidate Alzheimer’s disease drugs should be tested in human nerve cells rather than laboratory animals.

In the brains of patients with Alzheimer’s disease beta-amyloid protein deposits form that are deleterious to nerve cells. Scientists who work for drug companies are trying to find compounds that prevent the formation of these deposits. In laboratory mice that have a form of Alzheimer’s disease, over-the-counter drugs called NSAIDs (non-steroidal anti-inflammatory drugs), which include such population agents as aspirin, Tylenol, Advil, Nuprin and so on prevent the formation of beta-amyloid deposits. However in clinical trials, the NSAIDs royally flopped (see Jaturapatporn DIsaac MGMcCleery JTabet N. Cochrane Database Syst Rev. 2012 Feb 15;2:CD006378).

Professor Oliver Brüstle, the director of the Institute for Reconstructive Neurobiology at the University of Bonn and Chief Executive Officer of Life and Brain GmbH, said, “The reasons for these negative results have remained unclear for a long time.”

Jerome Mertens, a former member of Professor Brüstle’s research, and the lead author on this work, said, “Remarkably, these compounds were never tested directly on the actual target cells – the human neuron.”

The reason for this disparity is not difficult to understand because purified human neurons were very difficult to acquire. However, advances in stem cell biology have largely solved this problem, since patient-specific induced pluripotent stem cells can be grow in large numbers and differentiated into neurons in large numbers.

Using this technology, Brüstle and his collaborators from the University of Leuven in Belgium have made nerve cells from human patients. These cells were then used to test the ability of NSAIDs to prevent the formation of beta-amyloid deposits.

According to Philipp Koch, who led this study, “To predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells.”

Nerve cells made from human induced pluripotent stem cells were completely resistant to NSAIDs. These drugs showed no ability to alter the biochemical mechanisms in these cells that eventually lead to the production of beta-amyloid.

Why then did they work in laboratory animals? Koch and his colleagues think that biochemical differences between laboratory mice and human cells allow the drugs to work in one but not in the other. In Koch’s words, “The results are simply not transferable.”

In the future, scientists hope to screen potential Alzheimer’s disease drugs with human cells made from the patient’s own cells.

“The development of a single drug takes an average of ten years,” said Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer’s medications could be greatly streamlined.”

Stem-Based Treatment of Stoke

When blood flow to the brain ceases as the result of a blood clot, trauma, or injury, the brain suffers from a shortage of oxygen. Such an incident is known as a stroke and it can result in the death of neurons and the loss of those functions to which the dead neurons contributed. Treatment for stroke is largely supportive, but regenerative treatments that replace the dead neurons would be the most ideal treatment.

A research consortium at Lund University in Lund, Sweden has found that neurons made from induced pluripotent stem cells integrate into the brains of mice that had suffered strokes. This experiment takes a closer step towards the development of a regenerative treatment for strokes.

Strategies for stem cell-based regenerative therapy in neurodegenerative diseases.
Strategies for stem cell-based regenerative therapy in neurodegenerative diseases.

In the aftermath of a stroke, nerve cells in the brain die. At the Lund Stem Cell Center, the research groups of Zaal Kokaia and Olle Lindvall teamed up to develop a stem cell-based method to treat stroke patients.

After a stroke, the cerebal cortex tends to take the bulk of the damage and neuron loss from the cerebral cortex underlies many of the symptoms following a stroke, such a paralysis and speech problems. The method developed by the Lund Institute scientists should make it possible to generate nerve cells for transplantation from the patient’s own skin cells.


First, the Lund team isolated skin fibroblasts from the afflicted mice and used genetic engineering techniques to convert them into induced pluripotent stem cells (iPSCs), which have many of the differentiation capabilities of embryonic stem cells. These iPSC lines were differentiated into cortical neurons, which tend to populate the cerebral cortex. However, transplanting fully differentiated neurons into the brain tend to not work terribly well because the mature neurons are unable to divide and have poor abilities to connect with other cells. Therefore, the neuron progenitor cells that will give rise to cortical neurons are a better candidate for transplantation.

After generating long-term self-renewing neuroepithelial-like stem cells from iPSCs in the laboratory, the Lund group scientists showed that these stem cells could give rise to neural progenitors that expressed the types of genes found in mature cortical neurons. When these neural progenitor cells were transplanted into rats that had suffered strokes, two months after transplantation, the cortically fated cells showed less proliferation and more efficient differentiation into mature neurons with the right shape, size, and structure of cortical neurons and expressed the same proteins as cortical neurons. These tranplanted cells also extended more axons than those cells that were not fated to form cortical neurons. Transplantation of both the cortical neuron-fated and non-cortical neuron-fated cells caused recovery of the impaired function in the stepping test in comparison to controls. At 5 months after stroke, there was no tumor formation and the grafted cells had all the electrophysiological properties of mature neurons and showed full evidence that they had integrated into the existing neural circuitry.

These results are very promising and represent a very early but important step towards a stem cell-based treatment for stroke in patients. Further experimental studies are necessary if these experiments are to be translated into the clinic in a responsible way.

Stephen Hawking Visits UCLA Stem Cell Laboratory

Stephen Hawking
Stephen Hawking

On Tuesday, Stephen Hawking toured a stem cell laboratory where scientists are studying ways to slow the progression of Lou Gehrig’s disease, a neurological disorder that has left the British cosmologist almost completely paralyzed.

After the visit, the 71-year-old Hawking urged doctors, nurses and staff at Cedars-Sinai Medical Center to support the research.

Hawking recalled how he became depressed when he was diagnosed with the disease 50 years ago and initially didn’t see a point in finishing his doctorate. But his attitude changed when his condition didn’t progress as fast and he was able to concentrate on his studies.

“Every new day became a bonus,” he said.

The hospital last year received nearly $18 million from California’s taxpayer-funded stem cell institute to study the debilitating disease also known as amyotrophic lateral sclerosis. ALS attacks nerve cells in the brain and spinal cord that control the muscles. People gradually have more and more trouble breathing and moving as muscles weaken and waste away.

There’s no cure and no way to reverse the disease’s progression. Few people with ALS live longer than a decade.

Diagnosed at age 21 while a student at Cambridge University, Hawking has survived longer than most. He receives around-the-clock care, can only communicate by twitching his cheek, and relies on a computer mounted to his wheelchair to convey his thoughts in a distinctive robotic monotone.

A Cedars-Sinai patient who was Hawking’s former student spurred doctors to invite the physicist to glimpse their stem cell work.

“We decided it was a great opportunity for him to see the labs and for us to speak to one of the preeminent scientists in the world,” said Dr. Robert Baloh, who heads the hospital’s ALS program.

Cedar-Sinai scientists have focused on engineering stem cells to make a protein in hopes of preventing nerve cells from dying. The experiment so far has been done in rats. Baloh said he hopes to get governmental approval to test it in humans, which would be needed before any therapy can be approved.

Hawking is famous for his work on black holes and the origins of the universe. His is also famous for bringing esoteric physics concepts to the masses through his best-selling books including “A Brief History of Time,” which sold more than 10 million copies worldwide. Hawking titled his speech to Cedars-Sinai employees “A Brief History of Mine.”

Despite his diagnosis, Hawking has remained active. In 2007, he floated like an astronaut on an aircraft that creates weightlessness by making parabolic dives.

Doctors don’t know why some people with Lou Gehrig’s disease fare better than others. Dr. Baloh said he has treated patients who lived for 10 years or more.

“But 50 years is unusual, to say the least,” he said.

Human Neurons Derived from Adult Brain Cells

A research group from Mainz, Germany have discovered a protocol that can reprogram a particular type of brain cell from human brains into new neurons.

Within the brain, neurons are the cells responsible for nerve impulses. Learning and memory, personality, volition and responses to stimuli are functions of neurons. When large numbers of neurons die, the patient suffers and their memory leaves them, their personality changes, or worse. Neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease cause the death of large numbers of neurons and it is the death of neurons that is responsible for the symptoms of disease like these.

Benedikt Berninger, a faculty member of the Institute of Physiological Chemistry, at the Johannes Gutenberg University Mainz, Germany, and the senior author of this research said, “This works aims at converting cells that are present throughout the brain but themselves are not nerve cells into neurons. The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and provide a novel strategy for repairing the injured or diseased brain.”

The cells used by Berninger’s laboratory are known as “pericytes.” Pericytes are found in close association with blood vessels and are important in maintaining the blood-brain-barrier. Pericytes have also been shown to play a role in wound healing in other parts of the body.

Berninger chose pericytes for his research because he wanted to “target these cells and entice them to make nerve cells,” so that he and his research team could “take advantage of this injury response.”

When the converted neurons were subjected to further tests, they produced the normal types of electrical-chemical signals usually found in neurons, and also extended their connections to other neurons. This provided evidence that the converted cells could integrate into neural networks.

In their paper (Karow, et al., Cell Stem Cell 2012 11(4): 471), Berninger’s team write, “While much needs to be learnt (sic) about adapting a direct neuronal reprogramming strategy to meaningful repair in vivo, our data provide strong evidence for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons.”

Neurons Derived from Cord Blood Cells

A research group at the Salk Institute in San Diego has discovered a new protocol for converting umbilical cord blood cells into neuron-like cells. These new cells could prove valuable for the treatment of a wide variety of neurological conditions, including stroke, traumatic brain injury and spinal cord injury.

Physicians have used umbilical cord blood for more than 20 years to treat many different types of illnesses, including cancer, immune disorders, and blood and metabolic diseases. However, these Salk Institute researchers demonstrated that cord blood (CB) cells can be differentiated into cell types from which brain, spinal and nerve cells arise.

Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, who led the research team, said: “This study shows for the first time the direct conversion of a pure population of human cord blood cells into cells of neuronal lineage by the forced expression of a single transcription factor.”

Izpisua Belmonte’s group used an engineered retrovirus to introduce a gene called Sox2, a transcription factor that acts as a switch inside cells that converts them into neurons. Therefore, by introducing Sox2 into CB cells, and culturing them in the lab, the cells formed colonies that expressed genes normally found in neurons.

Were these cells actual neurons or faux neurons? Cells might make neuron-specific genes, but they do not assemble those gene products into neuron-specific machinery, then they are not neurons. To if such cells are neurons, they should be able to manipulate the electrical charges across their cell membranes. But subjecting cells to electrophysiological tests, they determined that these new cells, which they called induced neuronal-like cells or iNCs, could transmit electrical impulses. This shows that the iNCs were mature and functional neurons. Next, they implanted these Sox2-transformed CB cells to a mouse brain and found that they integrated into the existing mouse neuronal network and were capable of transmitting electrical signals like mature functional neurons.

Mo Li, a scientist in Belmonte’s lab and a co-first author on the paper, said: “We also show that the CB-derived neuronal cells can be expanded under certain conditions and still retain the ability to differentiate into more mature neurons both in the lab and in a mouse brain. Although the cells we developed were not for a specific lineage-for example, motor neurons or mid-brain neurons-we hope to generate clinically relevant neuronal subtypes in the future.”

Scientists can use these cells in the future to model neurological diseases such as autism, schizophrenia, Parkinson’s or Alzheimer’s disease.

CB cells offer several advantages over other types of stem cells. First, they are not embryonic stem cells and are not controversial. They are more plastic, or flexible, than adult stem cells from sources like bone marrow, which may make them easier to convert into specific cell lineages. The collection of CB cells is safe and painless and poses no risk to the donor, and they can be stored in blood banks for later use.

“If our protocol is developed into a clinical application, it could aid in future cell-replacement therapies,” said Li. “You could search all the cord blood banks in the country to look for a suitable match.”