The Questions of Developmental Biology

Fetal Neurons in Adult Hosts
In 1976,Lund andHauschka implanted fetal rat brain tissue into the brain of a newborn
rat. The fetal neurons made the appropriate connections within the host brain. This study offered
the possibility that transplants of fetal neurons might be able to repair damaged regions in human
brains.
There are many neural degenerative diseases, and Parkinson disease is one of the most
prevalent, afflicting about a million Americans. In Parkinson disease, dopamine-producing
neurons of the substantia nigra (a cluster of cells in the brain stem) are destroyed, and their axon
terminals in the caudate nucleus and putamen (two brain nuclei) degenerate. This leads to muscle
tremors, difficulty in initiating voluntary movements, and problems in cognition. The injection of
l-dopa (which the body metabolizes into dopamine) relieves the symptoms temporarily, but l-
dopa loses its effect with prolonged use, and it sometimes has adverse side effects.
In 1990, Lindvall and colleagues implanted human neural cells from the substantia nigra
of 8- to 9-week fetuses into a patient with Parkinson disease. The donor and recipient did not
need to be related, since the brain is separated from the immune system by the blood-brain
barrier, which shelters tissue implanted there from rejection by the immune system. Within 5
months, the transplant had restored much of the dopamine normally made by the substantia nigra,
as well as the patient's capacity for voluntary movement. Other laboratories have reported similar
restoration of function following the transplantation of fetal neurons into Parkinson patients
(Freed et al. 1992; Spencer et al. 1992). According to Björkland (1987), the optimal donor tissue
is that containing presumptive dopamine-secreting neurons that have undergone their last cell
division, but have not yet formed extensive synaptic connections. In 1992, Widner and colleagues
showed that grafts from fetal mesencephalons were able to restore motor functions in two patients
who had destroyed their substantiae nigrae by injecting themselves with synthetic heroin
contaminated with the by-product MPTP. This compound had created a condition that resembled
severe Parkinson disease.
Two recent studies have shown that fetal human cell transplants are not the only way to
restore the functional anatomy of the substantia nigra in Parkinson patients. First, studies by
Isacson and colleagues (1995) have suggested that the donor embryonic cells need not be human.
Embryonic pig mesencephalon cells reconstructed the normal neuronal connections when injected
into the striata of adult rats with a Parkinson-like disease. Second, when Gash and colleagues
(1996) injected GDNF into the cerebra of monkeys in which Parkinson-like syndromes had been
induced with MPTP, the monkeys showed a functional recovery from their symptoms. Moreover,
dopamine concentrations and numbers of dopamine-producing neurons in their brains increased
substantially. Since Parkinson disease is progressive, it is not known whether the grafted or newly
divided neurons will fall victim to the same disease process that destroyed the endogenous
neurons (Kordower et al. 1998; Hauser et al. 1999). However, it appears likely that fetal grafts
and new neurons are able to reestablish the synaptic connections that the destroyed neurons once
made.
In recent years (see Chapter 12), it has become evident that even the adult central nervous
system contains pluripotent neural stem cells. Research is underway to culture these cells in the
hopes of transplanting a patient's own neural stem cells into the damaged region of the brain
(Ourednik et al. 1999).