Readers should keep in mind, that this very informative background Bulletin article on Professor Boyd's thymus breakthrough, is dated 10 Oct 2001.
Bulletin article on the background of the thymus discovery
IMMUNE STRUCK
An Australian scientist's curiosity about a gooey substance in a tea strainer may ultimately lead to a breakthrough in the search for a cure for mankind's most lethal diseases. Graeme O'Neill reports.
As a budding first-year PhD student in 1973, Richard Boyd stood over a laboratory sink in the Department of Pathology and Immunology at Monash University Medical School in Prahran contemplating the chewing gum-like substance coating a mesh tea-strainer in his hand.
When Boyd or his colleagues sieved ground-up mouse thymus glands to extract their complement of white cells (T-cells), the stubborn, sticky residue had to be scrubbed off with hot water and detergent. What was it?
Boyd would discover the white goo consisted of cells that formed the spongy tissues of the thymus. Through a complex dialogue with these seemingly nondescript cells, blood stem cells migrating into the thymus from the bone marrow are transformed into T-cells and join the legions of the immune system that defend the body against infection and cancer.
When Boyd secured his first postdoctoral appointment at the University of Innsbruck in Austria in 1978, the thymus was still terra incognita, so he staked a claim.
By the time he returned to Australia to take up a research post at Monash University Medical School five years later, he had become a respected authority on the thymus. For the next 16 years, he and his Monash colleagues continued to map its microanatomy and decipher the complex steps by which the thymus transforms unspecialised bone marrow stem cells into mature T-cells.
In 1999, 26 years of meticulous work paid off with a discovery that could revolutionise the treatment of medicine's most intractable diseases.
Boyd has shown it is possible to regrow the near-dormant adult thymus and restore it to full, vibrant function – effectively, to make the immune system young again.
His technique involves drugs called GnRH blockers that have been used safely for more than a decade to help treat breast and prostate cancers, and endometriosis. The compounds mimic gonadotrophin-releasing hormone (GnRH), which rhythmically stimulates the pituitary gland in the brain to transmit a hormonal signal that induces the ovaries to release oestrogen, or the testes to release testosterone.
By overstimulating the pituitary, the drugs invoke a feedback loop that disrupts the signal to the gonads, temporarily blocking the release of sex hormones.
Cancer therapists use GnRH agonists to deprive breast cancers of the oestrogen that fuels their rampant growth, and to starve prostate tumours of testosterone.
But as Boyd showed two years ago in aged male mice - and recently, in a dozen ageing Melbourne men with prostate cancer – GnRH blockers have a surprising side effect. By temporarily squelching the sex hormones, they allow the thymus to regrow and regain full function.
Boyd's achievement brings one of immunology's glittering prizes within reach. Declining thymus function after puberty is implicated in an increasing risk of cancer with ageing, and may also explain why older people have problems fighting off infections, especially viral infections.
Only four decades ago, immunologists had no idea what the thymus gland did. Located behind the breast bone, in front of the heart, it blooms late in embryonic development, expands to the size of a fist in childhood, but, under the influence of surging sex hormones, shrinks to pea-size by late adolescence.
But in 1961, a young medical graduate of Sydney University, Dr Jacques Miller, proved that the thymus is one of the twin pillars of the immune system, a sort of school for infection- and cancer-fighting T-cells. Miller showed that mice thymectomised at birth are highly vulnerable to infection, and do not reject foreign skin grafts.
In the thymus, unspecialised blood stem cells are transformed into dendritic cells, helper-inducer T-cells and cytotoxic T-cells. Dendritic cells present antigens to helper T-cells for scrutiny; helper T-cells summon cytotoxic T-cells to destroy suspect cells displaying unfamiliar antigens that may be the products of mutant genes, or infectious microbes within.
In infancy the immune system encounters a host of unfamiliar antigens, and the distended thymus churns out legions of so-called naïve T-cells, primed to recognise and target anything alien. By adolescence, the immune system has acquired a vast repertoire of very long-lived "memory" T-cells, ready to be cloned by the billions in the event of later infections.
In adolescence, the thymus shrinks under the influence of surging sex hormones and the flow of naïve T-cells becomes a trickle. The immune system is slower to respond to new microbial threats – and, according to Boyd, less vigilant as ageing cells begin to display abnormal antigens that may be harbingers of cancer.
Like most medical researchers, Boyd started out working on young mice with enlarged, active thymus glands. At the time, the link between immunity and sex hormones was unsuspected, so they had the field almost to themselves.
But in the mid-1980s, someone else was keenly interested in rodent thymus function: Professor Marion Kendall established a large colony of aged rats at Cambridge University to investigate the links between the thymus, ageing, sex steroids and the neuro-endocrine system.
At a conference on the thymus in Europe in 1989, Boyd was intrigued when Kendall told him aged male rats regrew their thymus glands after being castrated. On returning to Monash University, Boyd established his own colony of aged mice, and began his own castration experiments.
Late in 1999, Boyd received a call from former CSIRO scientist Dr Geoff Grigg, who had read about his research in New Scientist magazine. "He told me, 'I like your science, but you know nothing about endocrinology'," says Boyd.
Grigg predicted GnRH agonists would have the same effect upon the thymus as surgical castration. Boyd procured a supply from a prostate cancer clinic at the Alfred Hospital next door, and tried it on his aged male mice. They promptly regrew their thymus glands, and began producing large numbers of T-cells.
Now Boyd has shown that GnRH blockers have the same effect in male prostate cancer patients.
But thymus pioneer Professor Jacques Miller, now a distinguished researcher at Melbourne's Walter and Eliza Hall Medical Research Institute, says the real significance of Boyd's discovery is that his mouse and human subjects are not merely recycling old, pre-programmed T-cells. Genetic tests show their rejuvenated thymus glands are pouring out naïve T-cells, primed to detect new, alien antigens.
His discovery comes at a time of dramatic progress in stem cell research and gene therapy. Thymus rejuvenation could open the way to a treatment foe some of medicine's most intractable diseases: cancer, HIV-AIDS, and auto-immune disorders like rheumatoid arthritis, lupus, and multiple sclerosis. It could also transform organ transplantation, by eliminating the problem of T-cell mediated rejection.
Of its potential to yield a cure for AIDS, Miller observes: "It wouldn't do any good just to regenerate the thymus, because the virus would simply reinfect the new T-cells. But if you could modify stem cells so they came out without the receptor for the virus, it would not be able to reinfect them."
That's just what Boyd is proposing: combining gene therapy and thymus therapy to restore the ravaged immune systems of AIDS patents
The human immunodeficiency virus (HIV) lays the body open to a host of opportunistic infections by killing off the helper T-cells that initiate the immune system's response to infection. The virus infects helper T-cells by attaching itself to a receptor called CD4, a vital component of the cellular communication system that co-ordinates the immune response. Deleting the CD4 receptor gene isn't an option – it would be as disastrous as the destruction of helper T-cells by the virus itself.
But Boyd believes it may be possible to cure AIDS by inserting genes that disrupt the virus's replication. On passage through a reactivated thymus, these modified cells would give rise to HIV-resistant helper T-cells and dendritic cells, capable of directing the full immune arsenal against the virus and other opportunistic infections.
Early in his career, Boyd investigated the thymus gland's suspected role in auto-immune disorders. Evidence has grown that certain auto-immune disorders result from T-cell programming errors in the ageing thymus.
"You don't see multiple sclerosis in kids, only in adults over the age of 20," he said. "Although you can't draw a direct line, the decreasing quality of T-cells seems to coincide with increasing susceptibility to auto-immune diseases."
Recent research implicates a phenomenon called antigenic mimicry in the onset of certain auto-immune disorders like arthritis, lupus and multiple sclerosis. Like chameleons, some microbes evade the immune system by cloaking themselves in antigens closely resembling those of the body's own tissues.
Self-reactive T-cells are normally deleted in the thymus before they mature, but from adolescence, the shrinking thymus produces progressively fewer new T-cells.
Boyd says persistent infection by a "mimic" microbe may overload the immune system; even after eliminating the agent provocateur, it continues to attack the tissues it was mimicking. Many patients who develop immune-system disorders like lupus or arthritis report suffering persistent flu-like symptoms in the preceding six months – signs of a hyperactive immune system.
The remedy could be as simple as removing the self-reactive T-cells, then rejuvenating the thymus to restore the immune system's ability to make subtle discriminations between "self" and mimic antigens.
Boyd says self-reactive T-cells may also be involved in allergic disorders, including severe allergies to foods like shellfish and peanuts. "We could treat people aggressively with anti-T-cell therapy to rule off the malfunction, then reactivate the thymus so the new T-cells would behave next time around."
Restoring the thymus could also save the lives of many cancer patients. Doctors treating leukaemia patients confront a dilemma: aggressive chemotherapy is required to destroy the bone marrow source of the leukaemic cells, but leaves patients vulnerable to opportunistic, lethal infections before a bone marrow graft can restore their immune function.
A tissue mismatch can also trigger a deadly graft-versus-host reaction in the weakened patient. Boyd believes new regulatory T-cells produced in the rejuvenated thymus could dampen the donor T-cell attack on the patient.
Adult patients who receive bone marrow grafts are vulnerable to opportunistic infections because they never regain full T-cell function. Boyd says thymus therapy could reduce the risks by rapidly rebuilding both T-cell and antibody-mediated immunity.
Thymus therapy could even solve the mismatch problem in organ transplantation, says Boyd. "You'd give the patient some of the donor's own haemopoietic [bone marrow] stem cells at the time of the operation. In the thymus, some would become dendritic cells that would delete any new T-cells reactive to the transplanted organ.
"We've already done it successfully in rodents. It's no longer a question of whether it will work, but how to make it work. Of course, we now have to make it work in humans."
In childhood and early adolescence, the thymus produces huge numbers of naïve T-cells that, by destroying any mutant cells displaying abnormal proteins, literally nip tumours in the bud – a phenomenon called immunosurveillance.
Recent research suggests that waning T-cell numbers allow some of these abnormal cells to evade detection, accounting for the rising risk of cancer from early adulthood to old age.
Dr Joe Trapani, an oncologist at Melbourne's Peter MacCallum Cancer Research Institute, says Boyd's idea of using thymus therapy to restore the immune system's cancer-detection function is "not outlandish".
"Most of the evidence from humans is anecdotal," says Trapani. "But we have been working with rodents, and shown clearly that the theory is sound."
That, says Trapani, gives hope that novel therapies to boost the immune system, and anti-cancer vaccines, will be effective in treating cancer.
"But what Richard is trying to do is more fundamental," says Trapani. "He is looking at why the process is not preventing cancer – it's an unproven but reasonable hypothesis that if you could broaden the way T-cells function in adults, you could not only treat cancer, but reduce its prevalence."
So broad are the potential applications of thymus rejuvenation that Norwood Abbey, the small Melbourne-based biotechnology company that purchased the intellectual rights to Boyd's discovery late last year, has decided on the advice of its patent lawyers not to publish his data in the medical research literature – at least not yet.
Norwood Abbey's business and development director, Peter Simpson, chanced upon Boyd's research at Monash University last November while talking to medical students about his company's plans to commercialise novel drug-delivery systems. Boyd was in the lecture theatre, and asked several questions that set Simpson's antennae humming.
"Richard's work had a significant drug-delivery component to it," says Simpson. "But as we talked, it became obvious to me that he was on a very different wavelength – he believed he could rejuvenate the immune system.
"We had to act very quickly – Richard hadn't got around to renewing his provisional patent, and it was due to run out in 10 days."
On Simpson's hunch, Norwood Abbey took a leap of faith. Over the next week, its lawyers worked feverishly to solidify the patent. The renewal papers were posted at the only 24-hour post office in the US, at LA International Airport, the night before the deadline.
Simpson believes the fact that Boyd has already tested the therapy on humans gives Norwood Abbey at least a two-year lead on any competitor.
And it's well-placed to negotiate with potential suitors: it has a valuable patent, and pharmaceutical companies are salivating at the prospect of finding a lucrative new market for GnRH blockers, which will soon come out of patent. With their proven safety and efficacy, makers would not have to ante up the typical $300m to $500m cost of steering an experimental drug through the US Food and Drug Administration's regulatory maze.
