By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
Say the word "dopamine," and people tend to think of Parkinson's disease - caused by a lack of that major neurotransmitter in the brain, and treated by its replacement. Conversely, an excessive amount of dopamine is deemed by many to be responsible for the onset of schizophrenia.
So far, that rationale - first posited in 1967 - has remained an unproven hypothesis. Now it's confirmed by an article in the July 4, 2000, Proceedings of the National Academy of Sciences (PNAS). Its title: "Increased baseline occupancy of D2 receptors by dopamine in schizophrenia." Its authors are research psychiatrists at Columbia University College of Physicians and Surgeons in New York, and brain-imaging specialists at the New York State Psychiatric Institute. They measured, for the first time in living subjects, the presence of dopamine in the brain striata of 18 patients with schizophrenia and 18 matched controls. Their study compared D2 in brain synapse availability before and after its acute depletion by psychoactive drugs used to medicate the disease.
The co-authors found that this depletion produced overstimulation of the dopamine receptor in 19 percent of patients vs. 7 percent in controls. This increase in that major chemical messenger took place both in naove, never-medicated subjects, and in previously treated chronic patients experiencing an episode of illness exacerbation. Moreover, this jump in synaptic dopamine predicted good treatment response of symptoms to antipsychotic drug therapy.
The data showed that excess amounts of dopamine accompany the onset of a schizophrenia attack, and is not a side effect of drug treatment. On the contrary, the findings demonstrated that a six-week round of drug treatment markedly reduced hallmark psychotic symptoms - including delusions, hallucinations, thought disorganization and paranoia - mostly in patients with high dopamine levels. But there was no correlation with improvement in social, emotional and cognitive symptoms, such as memory loss.
"These results show for the first time," the paper's lead author pointed out, "that dopamine levels are abnormal in the brains of most patients suffering from this illness. The goal now is to complete the picture, and determine whether other neurochemicals are implicated in the disease process of those people who have normal dopamine levels."
A commentary accompanying the PNAS paper, "Schizophrenia: More dopamine, more D2 receptors," notes that the disease afflicts 1 percent of the world's population, and usually sets in during early adulthood. While modern drugs ameliorate the lives of victims, it pointed out, the cause of the schizophrenia remains unknown. What is known, it added, is that "the dopamine2 receptor is the primary site of action for all antipsychotics, including clozapine [Clozaril] and quetiapine [Seroquel]."
Embryonic Stem Cell Technique Churns Out Dopaminergic Neurons 'In Unlimited Numbers'
In Parkinson's disease (PD), it's the depletion of dopamine, not its excess, that must be corrected clinically. In current PD therapy, a drug called L-dopa replaces the brain chemical lost to dying dopaminergic neurons, but the effectiveness of this supplementation wanes with time. A still-experimental - and controversial - gene-therapy approach implants fetal brain cells into the brains of PD patients. But these tissues are in understandably short supply, and stem cells are being researched as alternative sources of dopamine-producing neurons.
One recent preclinical approach is reported in the June 2000 issue of Nature Biotechnology, under the title, "Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells." Its authors are at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Md.
They point out, "Embryonic stem (ES) cells are capable of adopting all the cell fates in a developing embryo," and describe "a method for obtaining dopaminergic and serotonergic neurons in high yield from mouse ES cells in vitro." Their preclinical system for producing dopamine and serotonin neurotransmitters, the co-authors suggest, "provides a powerful tool for potentially understanding and treating neurodegenerative and psychiatric diseases. The neurons that synthesize these transmitters," they observe, "are generated by developmental signals around the boundary between the midbrain and the hindbrain."
Their journal paper makes the point that "the central finding of this study is that midbrain and hindbrain neurons can be generated in unlimited numbers from ES cells. For every 3 X 106 of ES cells, we obtain 7 X 106 dopaminergic . . . and 103 of these grafted neurons lead to behavioral recovery in a rat model of Parkinson's disease." The yield of dopamine-producing neurons, they state, is the highest ever obtained from tissue biopsies or in vitro culture.
Data From Mice, Humans Suggest Bone-Marrow Stem Cells Can Generate Transplantable Liver Cells
The liver - the largest organ inside the human body - is famous for its ability to regenerate most of its bulk, after trauma or disease. But there are limits to this hepatic virtuosity - ergo, liver transplants. So histopathologists at the Imperial College School of Medicine in London, resorted to non-hepatic, adult - not fetal - stem cells. The title of their brief communication in Nature dated July 20, 2000, says just that: "Hepatocytes from non-hepatic adult stem cells."
The paper shows that "adult human liver cells can be derived from stem cells originating in the bone marrow, or circulating outside the liver, raising the possibility that blood-system stem cells could be used clinically to regenerate hepatocytes [liver cells] for replacing damaged tissue." The co-authors' transplantation experiments in mice "indicated that some hepatocytes have the stem cell-like property of massive division potential." This suggested that "hepatocytes themselves are the principal progenitor cells for new hepatocytes."
Based on this murine data, the co-authors turned to the human condition. They tested the livers of nine female patients who had received bone marrow transplants from male donors, and detected the growth of new hepatocytes carrying male-determining Y chromosomes. Similarly, in autopsies on another 11 women who had donated transplant livers to male recipients, they found Y-positive hepatocytes after those donor organs had been removed by reason of recurrent disease. These experiments confirmed that "circulating extrahepatic stem cells of endogenous, as well as exogenous, origin, can colonize the liver. Our results," the co-authors concluded, "should contribute to the development of human tissue for use in a therapeutic context."