Since the late 1990s, Lawrence Goldstein has been passionate about the promise of research with human embryonic stem cells—pliable, generic cells from the early embryo that scientists can convert into the body’s specialized cells to study basic biological processes, disease, and organ regeneration.
Goldstein became such an advocate for stem cells he helped write the California proposition that created a $3 billion funding organization in 2005 to support human stem cell research in the state. Voters supported the initiative because human embryonic stem cell research has been curtailed nationwide; the federal government has limited its financial support of research with these cells, citing the ethical problem of destroying embryos in performing the investigations.
When Goldstein first started promoting human embryonic stem cell research, he was acting to support the freedom of scientific inquiry to benefit society. Recently, though, Goldstein, funded by the Howard Hughes Medical Institute and the California program, has begun using human embryonic stem cells in his own laboratory. His research may demonstrate another example of the value of embryonic stem cells by helping to identify the cause of Alzheimer’s disease.
Goldstein studies the cellular machinery that moves material inside nerve cells and how problems with these conveyance systems might lead to Alzheimer’s and other neurodegenerative diseases. Embryonic stem cells, he says, are the only source of healthy human brain cells for his research. Extracting nerve cells from a living human brain for experimentation cannot be done.
To study normal and abnormal transport mechanisms inside nerve cells, Goldstein transforms the human embryonic stem cells into brain cells. He also gives the embryonic stem cells genes implicated in the transportation problems and compares the behavior of the cells with the new genes to those without the genes.
Research from Goldstein’s laboratory suggests that in the nerve cells of people with Alzheimer’s, too much of a normal protein, called amyloid precursor protein, might interfere with the movement of important biochemicals inside the cell. Chemical cargos, transported by a protein complex that includes kinesin (which Goldstein first cloned in the fruit fly in 1988), move from their site of manufacture near the cell nucleus down the axon, a nerve cell thruway, to the synapse, where neurons release chemicals to communicate. A blockage of the normal traffic flow is the primary cause of harm to brain cells in Alzheimer’s disease, Goldstein believes.
His theory challenges the prevailing hypothesis about the cause of Alzheimer’s, which says an excess of the toxic amyloid-beta peptide, derived from an amyloid precursor protein surplus, leads to damage of the cells. The peptide ultimately forms the characteristic agglomerations in Alzheimer’s patients’ brains called plaques. Goldstein, however, has evidence that the traffic problems precede the peptide’s toxicity. Research is ongoing in his laboratory, which, if correct, would offer new approaches to disease treatment.
Goldstein has been studying the movement of material inside cells since graduate school. For his Ph.D., which he obtained in 1980, he employed genetics in the fruit fly to study how chromosomes, the carriers of genes, move to two daughter cells when cells divide. “The process turned out to require a complicated system of motor proteins and tracks,” Goldstein says. Motor proteins move along a track by breaking down the molecule ATP for energy.
As an independent investigator at Harvard from 1984 until 1993, Goldstein defined the structure and organization of an important type of motor protein, called kinesin, which exists in different forms in different cells and organisms. Cells use some subtypes to move chromosomes, while nerve cells use others to help deliver cargo down the axon.
Goldstein realized that drugs targeting cell division kinesins could be potential anticancer agents because they would stop cancer cells from dividing. He helped develop such drugs, which are being tested in patients.
In 1998, Goldstein began to focus on kinesins in nerve cells and their role in disease. He thinks amyloid precursor protein in healthy people may be part of a complex of proteins that attach cargo to the kinesin motors in nerve cells. But if there is an excess of amyloid precursor protein or a problem with the protein, as happens in Alzheimer’s, then the kinesin motors fail somehow, and cellular movement becomes impaired.
Goldstein is pleased his findings about kinesins in cell division might lead to a new drug against cancer. He also takes pride in his stem cell leadership, and in 2006 he was named director of the Stem Cell Research Program at San Diego. He now hopes his past successes with kinesins and stem cell policy have him on the right track to improve understanding of Alzheimer’s disease.
