Richard Palmiter

Palmiter's research career began with the role of sex steroids and the regulation of the transcription of genes responsible for egg white production in laying hens. This research surrounding the regulation of gene transcription led him and his team to focus more specifically on the regulation and function of metallothionein genes: gene products that bind heavy metals and are believed to have a role in metal homeostasis and resistance to metal toxicity and oxidative damage. This research is notable as his group was the first to clone these specific genes and the group has later gone on to dissect the regulatory elements involved in their expression. His background in zoology allowed him to lead his team to generate mice that make excess metallothionein or mice that are unable to make specific metallothionein proteins as a means of exploring the gene function in animals.[2]

Palmiter's most well-known work involves his studies on making transgenic mice. This research was conducted in a 15-year transcontinental collaboration with Ralph L. Brinster at the University of Pennsylvania. These researchers were pioneers in introducing functional genes into the genome of mice, rabbits, sheep, and pigs—these animals with foreign genes inserted into their genomes are labeled transgenic. Palmiter and Brinster created the ‘super mouse.’ This mouse grew larger than normal as a result of adding a hybrid gene to the mouse genome. The mice carried a growth hormone gene that was controlled by the regulatory elements of the aforementioned metallothionein gene. Prior to their work, the term ‘transgenic’ was virtually unheard of; but after their collaboration, the use of the word in scientific papers has skyrocketed.

DNA sequences important for the restriction of gene expression to specific cell types were discovered due to these newly created transgenic mice. These mice were also used for studying cell transformation and cancer. Palmiter's research group also uses gene knockout techniques to inactive genes with the primary responsibility of chemical transmitter synthesis that is vital for studying the nervous system development and function. Their research has concluded that noradrenaline is essential for normal maternal behavior and defense against cold stress: mice that cannot generate neuropeptide Y eat and grow normally but they are alcoholic and have a tendency to have epileptic seizures.[2]

Palmiter and his research group have also investigated the role of zinc as a chemical transmitter in the brain.  They have discovered that it prevents excessive excitability of the CNS. Mice that do not make dopamine are found to be hypoactive and have no motivation to eat or drink. Despite their lack of thirst or hunger, these mice can be kept alive with pharmacological delivery of L-DOPA or viral gene therapy with vectors that restore L-DOPA synthesis.[3] The group's recent research has turned to the attempt to enhance understanding of Parkinson's disease. The underlying cause of PD is a gradual loss of neurons that produce dopamine.  Palmiter's current ideas suggest that the disruption of mitochondrial function and the accumulation of damaged proteins has the potential to lead to the death of dopaminergic neurons. Their current task is developing models to mimic these cellular processes.[4]

In the last three decades Palmiter has become interested in the neural circuits that control innate behaviors such as eating and drinking. Palmiter and his team use mouse genetic models and viral gene transfer to study neural circuits in specific brain regions. Their goals are to visualize where relevant neurons are located and where they project their axons, to record the neurons’ activity in real time, and to evaluate the behavioral and physiological consequences of activating or inhibiting those neurons. They also aim to identify downstream targets of certain neurons and discern how they are involved in responding to various threats, including pain, itch, and food poisoning. [5]