Gus Nossal: It’s Australian Jacques Miller’s turn for a Nobel Prize

Jacques Miller discovered the function of the thymus gland, which changed immunology forever.

Every year at the beginning of October, a frisson runs through the global medical research community. Who will win the greatest lottery of them all, the Nobel Prize for Medicine?

In a cynical and sceptical world, here is one status symbol that has not lost its magic.

This year, the matter has an extra piquancy for Australia. The media has speculated that it might at last be the turn of Walter and Eliza Hall Institute’s (WEHI) Professor Jacques Miller, whom I’ve previously described as the single living individual most deserving of a Nobel Prize, to receive it.

A large claim? Let’s examine the facts.

The unknown organ

Before Miller’s work, the thymus gland represented a deep mystery.

It’s a large gland situated behind the breastbone, sitting in front of the heart.

Gray's Anatomy, 1918.

When examined under the microscope, the thymus gland contains billions of small round cells that look just like white blood cells known as small lymphocytes.

Electron microscopic image of a single human lymphocyte. National Cancer Institute.

These lymphocytes also occur in lymph nodes, the spleen, tonsils and adenoids and numerous other collections of lymphatic tissue.

Defence system

Past research had proven that lymphocytes from such lymphoid tissues were the main warriors of nature’s defence system, the immune system.

When properly stimulated with vaccine molecules (or antigens), they multiply, begin to form antibody molecules, or mount a direct attack on invading micro-organisms. This process is known as cell-mediated immunity.

Unknown function

Cells derived from the thymus had no such power to mount an attack, or were weak, at best.

And when the thymus was surgically removed in an adult mouse, its immune response wasn’t impaired. It was clear there was something very different about thymus lymphocytes compared with other lymphocytes.

Without any meaningful function for the thymus, scientists struggled to understand it. One idea was that it was a graveyard for dying lymphocytes.

Another was that it was some kind of evolutionary relic, like the appendix, without any present function.

But a line of research, which had little to do with cellular immunology, revealed a surprising fact about the thymus: when it was removed from mice, they didn’t develop certain forms of leukaemia.

Somehow the thymus was essential in the genesis of such leukaemias.

Initial investigations

Miller was interested in studying leukaemias that might have been associated with a virus. Thymus removal (thymectomy) in adult life did not prevent such leukaemias.

Noting that some of these leukaemias appeared very early in life, Miller taught himself to do thymectomies at younger and younger ages.

Finally, he managed to remove the thymus within just a few hours of the mice being born.

Bearing in mind that these little animals weighed less than a gram, this was an extraordinary feat. So was keeping the operated sucklings alive and stopping the mothers from eating them!

Jacques Miller, a “peerless experimentalist”, in his early career. WEHI

When the neonatally thymectomized mice grew up, several striking abnormalities were noted.

First, they were very prone to all kinds of infections, and actually failed to thrive in comparison to mice with thymus glands.

But when the mice were raised in a germ-free environment, their growth pattern was normal.

So their runt status was the result of their immune system’s failure to protect them from infections.

Miller then challenged their immune systems in various ways. He gave them standard vaccines and the responses were sub-normal.

He placed foreign skin grafts into their coats. These would normally be rejected within seven to 10 days, but in the neonatally-thymectomized mice, skin grafts survived and grew a luxurious growth of hair (he even grafted white skin on a black mouse).

Later in life, a disproportionately high percentage of the mice developed leukaemia and other cancers. This showed the thymus, in very young life, was critical to the correct development of the immune system.

It could be argued that the thymus was in fact the mastermind of the immune system.

In the crucial first days and weeks of the mouse’s life, it exported immunologically competent cells to the rest of the body.

As these colonised the various lymphoid tissues, living for a very long time, the thymus became less important.

Help arrives

In 1966, Miller was joined by a gifted veterinary science graduate who embarked on a PhD with him: Dr Graham F. Mitchell.

Together, they demonstrated that small lymphocytes – which all look so similar under the microscope – actually fall into two broad classes. These later came to be called T and B lymphocytes.

T cells are derived from the thymus and B cells from the bone marrow.

They showed it was actually the B cells that made the precious antibody molecules that keep us immune to many diseases; whereas the T cells were responsible for cell-mediated immune responses such as skin graft rejection or delayed hypersensitivity.

Most surprisingly, for many antibody responses, the T cells were actually needed to help the B cells in their task of antibody production.

Such novel and provocative findings were not accepted instantly.

Sir James Gowans, the doyen of British immunologists, long maintained that lymphocytes consisted of a single, uniform, homogeneous population.

While he recanted when the evidence became overwhelming, another senior immunologist, the Australian Professor Bede Morris never did. His immortal comment was that the only significance of B and T cells was that they constituted the first and last letters of the word “bulls**t”.

Miller’s key findings were independently confirmed fairly rapidly.

Impact of the discovery

Miller is the last person to discover the function of a human organ — the thymus — and not a single chapter of immunology has been untouched by the discovery.

T cells became even more prominent when it became clear that they were the chief target of the AIDS virus.

Miller continued to make discoveries about the thymus and T cells for many decades, including gaining important insights into:

  • how the immune system discriminates between self and non-self;

  • how it goes wrong in autoimmune diseases; and

  • how the whole orchestra of the immune system is regulated.

All of this is covered in 400 scientific papers.

Recent accolades

For the 50th anniversary of the first thymus findings (September 2011) Miller was asked to provide a summary of his life’s work for Nature.

Jacques Miller is now a WEHI Laureate and an Emeritus Professor at The University of Melbourne. WEHI

And in June 2011, The Walter and Eliza Hall Institute ran a celebratory symposium in Melbourne.

Is it possible that the venerable ladies and gentlemen of the Medical Faculty of the Karolinska Institute in Stockholm were reading and listening?

Miller’s work has been honoured by the international scientific community with several prizes: the Copley Medal, the Royal Society’s highest honour barring the Presidency; Germany’s top prize, the Paul Ehrlich-Ludwig Darmstaedter Prize; and Canada’s famous Nobel predictor, The Gairdner Foundation Annual International Award.

Those of us who have known Jacques for a lifetime didn’t need these external signals of his worth.

We esteem him as a peerless experimentalist, an inspiring research mentor, an embracer of impeccably high standards of scientific rigour and integrity. In short, Miller is a paragon of the noble profession of medical research which he graces.

Still full of ideas and vigour at the age of 80, long may he continue his life’s lofty mission.

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