By Peter Goldie
To further complicate the world of molecular biology in which he exists, Dr Andrew Perkins makes disconcerting references to "going back further in time".
Dr Perkins, who came to Monash on a Logan Fellowship 18 months ago after a four-year fellowship in paediatrics at Harvard University, makes forays into the earliest stages of life seeking master control genes. He tries to find them, understand them and adapt that understanding to real-time use in fighting disease.
The 'time' he goes back to is a stage in embryonic evolution when creatures such as frogs, mice and humans share the same cell types and body plan. He studies what happens after the creation of life and the division and separation of cells - the earliest determinants of every individual.
Embryonic stem (ES) cells are one of his most important tools. These cells have the remarkable capacity for unlimited growth in a tissue culture dish, but retain the ability to produce an entire living mammal when transplanted back into an early embryo.
As a bone marrow transplantation specialist at the Alfred Hospital in Melbourne, Dr Perkins is in constant touch with the reality of patients with leukemia, many of whom are undergoing bone marrow transplants. Back at his lab in the Physiology department at Monash, he is an internationally recognised authority who has just been awarded a Senior Research Fellowship with the Wellcome Foundation.
The Wellcome award comes after his analysis of two master control genes in mice. He used a 'gene knockout' model (removing a specific gene from ES cells and producing a mouse from it) to test the function of these control genes. The two genes have both been found to be critically important in blood development.
One of his few reservations with the progress of his work is the name attached to his discoveries: the Erythroid Kruppel-like Factor and the Basic Kruppel-like Factor.
"They're horrible names, aren't they?" he laughs. "I wish they had better names. And all the first one means is 'something in the red cells that looks like a bagel!'." (Erythroid = red cells; Kruppel = German for a type of bagel). But their simple names belie their importance.
Dr Perkins is on the trail of what produces healthy haemapoietic stem cells (HSC), the common precursor from which all the components of blood - red cells, white cells and platelets - develop. One of the main sites in the adult for their production is bone marrow.
The clinical spin-offs of understanding these genes could be hugely important. If master control genes that determine HSC production can be identified, then the growth of HSCs in a tissue culture dish could provide a potentially unlimited source of replacement HSCs for cancer sufferers who lose healthy HSCs during radiotherapy and chemotherapy.
With further work, healthy HSCs could be genetically tooled to incorporate self-recog-nition molecules, thereby switching off adverse reactions such as 'rejection' and 'graft-versus-host disease' (where the do-nated bone marrow attacks the cells of the recipient).
One of Dr Perkins's control genes - Erythroid Kruppel-like Factor (EKLF) - controls the type of haemoglobin in our red cells. "There is a normal switch that happens in human beings where the type of haemoglobin making up our red cells changes during our progression from embryonic life to adult life, just like switching a light on and off," he explains.
Scientists around the world have been trying to work out the causes of this switching for a decade or more.
It is extremely relevant for people with sickle-cell anaemia and thalassemia whose affected children are blood-transfusion dependent from birth and who will die as teenagers or young adults from a defect in the adult globin gene.
"If we could design a drug that could antagonise the EKLF switch protein, it could be given to patients with sickle-cell anaemia or thalassemia," Dr Perkins says. "We could reawaken the dormant normal foetal haemaglob gene, and these people would be basically cured."
Sickle-cell anaemia is a huge health burden for countries with significant Black populations - in the US health costs top $1 billion a year. Thalassemia affects other groups, particularly Italian and Greek populations. Monash is one of Australia's largest research and treatment centres for thalassemia.
The Wellcome Senior Research Fellowship represents an important expansion in
Dr Perkins's team's work. One of only four awarded this year, it represents
significant professional recognition as well as a boost
in funding for staff, research, equipment and conferences.
In coming years, the research on haematopoiesis in mice will be replicated in humans. Between now and then there is a minefield of ethical controversy awaiting the scientists. Human tests will require early embryonic material and to acquire such material for research into genetic engineering of any kind will no doubt fuel debate.
Bone marrow transplantation specialist Dr Andrew Perkins's work in identifying master control genes could have great importance in fighting a range of diseases.