The progress of molecular genetics

GREAT SCIENCE is characterised by discovery and by finding solutions to real problems. Unlike physics, where a prediction based in theory leads to a search for supporting evidence, progress in biology depends more on systematic experimentation and observation than on any grand hypothesis. This is because biological systems have sequentially and adaptively evolved via mutations in the designer code of our genes. Without an overarching theory, researchers are required to tease out the molecular details of how life works.

Crick and Watson’s seminal model for DNA structure has led to the new field of molecular genetics. Still in its infancy, the discipline has been moving from the research laboratories to applications that inform medical practice.

Those of us active in clinical practice, though familiar with the basic pathway from DNA to protein, are likely to have a limited understanding of molecular genetics, depending on our graduation vintage and our ability to keep up with the field. That is why it is worth spending a little time and money on award-winning science journalist Elizabeth Finkel’s new book.

It is intended for a lay audience; however, though still active in immunological research, I had many knowledge gaps filled by its easy style and personalised accounts.

What is your understanding of terms like genomics, histones, epigenetics, RNA interference? Is much of the genome still assumed to be comprised of useless “junk”? Not so, it seems, and Finkel tells us why. How useful is investigating the genetic basis of various cancers, and what progress has been made with the substantial research funding involved? We all know about BRCA1 and BRCA2 genes in breast cancer and test for them in practice, but what about genes possibly implicated in colon cancer? How has the idea of a genomically based “personalised” medicine evolved? Finkel tells us that there is a way to go, but the field is moving forwards.

The book covers a little of the early history and then moves on to explaining disease processes with an obvious basis in molecular genetics. Discussion is then broadened to how the DNA revolution might contribute to sustaining a probable 9 billion people on an increasingly environmentally challenged planet. Anyone who talks regularly with the public can benefit from this discussion, where there is an increasing focus on the supposed dangers of genetically modified foods. The book ends by inviting you to “Meet your ancestor”, retracing the long story of evolution of ourselves and other extant life forms.

The genome generation is thus a clear and accessible overview as well as a ready reference. From the era of great men and grand theories, biological science has moved on to a time when the latest experiment or datasets lead astute minds to consider every possibility. Finkel’s book gives a good understanding of how we are “instructed by nature” in the world of molecular genetics.

MJA Dr Eric Dark Creative Writing Prize – A good hairdresser

Highly commended

I took an immediate dislike to him when I met him 10 years ago. He had an irritating manner that annoyed me. He was middle-aged, short, solidly built with a swarthy complexion and carefully groomed dark hair greying at the temples. He rarely made eye contact and when he spoke his words seemed to slide out of the corner of his mouth.

He greeted his customers with a simple “Signor” and with a wave of his hand clasping his scissors indicated where to take a seat. Occasionally he would hail a passer-by on the street with a “Buongiorno!” and a wave of his scissors in the air. He rarely spoke otherwise. If he did it would be some caustic quip or grunt directed at the talkback radio show host on the loudly crackling radio in his small crowded shop. He showed little interest in his customers, preferring, it seemed, to stick to the job at hand or look out the window onto the street. Despite this lack of conversation and a lack of eye contact, his attitude seemed to me to indicate he was doing you a favour cutting your hair; take it or leave it, he didn’t give a damn.

His shop was across the road from the hospital where I had started a new busy job caring for critically ill children. Out of convenience I had him cut my hair on three or four occasions until, fed up with his manner, I found a hairdresser more to my liking.

For me it’s a very personal and often a pleasurable experience having a haircut. I can sit back in a comfortable chair, relax and, cocooned in a flowing drape, snooze or perhaps engage in idle chat for 20 minutes or more, and escape the demands and responsibilities of my hospital work dealing with sick children. A little conversation may be pleasant, but it isn’t necessary. Just to sit and doze while the hairdresser quietly snips, buzzes, shaves, combs and brushes in silence can be soothing beyond measure. I prefer to have the same hairdresser. Wherever I have lived I have sought out a hairdresser and, once found, I have loyally attended until either he or I have had to move on.

Recently my regular hairdresser, a pleasant enough although rather fastidious Englishman, whom I had taken some time to warm to, closed up shop and left without warning, leaving me with the need to find a new hairdresser.

Some weeks later when in need of a haircut I walked out of my local library and saw on the other side of the road a red and white barber’s pole and behind it a men’s hairdressing shop. Impulsively I stepped off the footpath, dodged through the busy road traffic and entered the shop.

There he was. I recognised him immediately. He must have moved shops. “Signor” he said and indicated with his scissors to take a seat. He gave no indication he recognised me, not that he would or should after so many years. He was a little grey, his face more lined, and his body more rotund but the same irritating manner remained. He still failed to make eye contact and still had an irritating offhand manner. I was tempted to leave but sat down where directed, picked up one of the few tattered magazines scattered on a grubby low table and waited my turn. His radio, set on a talkback radio show, crackled loudly just as it had done 10 years ago.

On one side of me sat a big red-faced flustered middle-aged man trying without success to restrain a small child. The child rocked backwards and forwards on his chair, climbed over the top of the chair, banged his hands on the magazine table and tore pages from the magazines. The child ignored his exasperated father’s pleas to behave. The hairdresser ignored them both.

Seated on my other side was an elderly, frail and sickly looking man leaning forward with his hands on his knees. His hair was sparse and uncombed and his skin wrinkled, pale yellow and loose. There was dried spittle on his lips and his jaundiced sunken eyes had a fearful haunted look. On his far side a young man sat with his right arm around the old man’s shoulder and spoke quietly to him. The old man occasionally nodded. Both seemed oblivious to the noise in the room from the child and the radio.

The child was next in line for a haircut. The hairdresser without a word looked directly at him and motioned to him with his scissors to come forward. The child became quiet instantly but clung to his father as the father carried him forward and placed him in the chair. The hairdresser quickly draped the child and began the haircut, ignoring the child’s furtive pleading glances towards his father. As the haircut progressed I watched the child in the mirror and saw his facial expression gradually change to wide-eyed interest in the hair falling about him. When completed the hairdresser lifted the child out of the chair, passed him to his father and, quickly looking towards the old man, indicated with his scissors that he was next.

The old man was helped slowly forward by the young man and gently eased into the hairdressing chair. Although his back was facing me I could clearly see his haunted yellow face in the large wall mirror in front of him.

The hairdresser turned the radio volume down and his manner seemed to completely change as he attended to the old man. I watched intently. Gone was the mute, who-gives-a-damn attitude. Replacing this was a look of the utmost kindness and concern as he carefully placed the drape around the man and gently applied the foamy lather to the man’s cheeks, chin and neck with a shaving brush. He spoke to him in a quiet caring voice as he slowly and carefully removed the creamy white foam with a cutthroat razor to expose the worn sallow cheeks. He continued to talk in a quiet monotone as he gently shaved the man’s chin and neck. Once completed he softly massaged the aftershave balm into this newly shaven neck and face. Finally he cut some stray hairs off the back of the man’s neck and gently combed and patted the unruly hair into place. Throughout all this the man would occasionally nod in response to the hairdresser’s soft words but said little, although the suffering face in the mirror seemed more relaxed. When finished, the hairdresser helped him slowly from the chair shook his hand and with a “Signor” passed him to the supporting arms of the young man and arm-in-arm they moved slowly out of the shop onto the street and gradually out of sight. There had been no payment. I was touched by this scene.

I was next in line. The radio volume was turned up. The tenderness left the hairdresser’s face as he tied the drape around my neck and not looking at me said “How do you want it done?”, followed by the old look I could see in the mirror . . . as if I care.

I think he must have been deep in thought about the old man or perhaps he had noticed me watching him because this man who had never made conversation with me suddenly said “My sister has cancer. She’s doing it tough, just like that old man. He’s got cancer that’s spread. He hasn’t got long. His son brings him along once a week so I can give him a shave”.

Just as he was finishing with me the telephone rang. He stopped, grabbed the phone and talking out of the side of his mouth I heard him say “Yeah. How old is the kid?” and then “Sure, I’ll come after work and give him a haircut, no problem” and then “What ward’s he on? 3B, sure, I know the cancer ward”.

I suddenly realised that my hairdresser, the man I thought didn’t give a damn about anybody, was going after work to the oncology ward of the children’s hospital where I worked to give a child a haircut. Once again I was touched by this man’s actions and ashamed for misjudging him. This man who can calm a misbehaving child, this man who shows great tenderness and kindness to a dying man and this man who goes to a children’s hospital after work to cut the hair of a child with cancer is surely a good man. I don’t care if he rarely talks or looks as though he doesn’t give a damn. I have found myself a good hairdresser and I’m going to stick with him.

Better performance metrics for the MJA

To the Editor: There is indeed a lot to “like” about the MJA in recent years,1 including a much-improved website, a defined space for the humanities, and the Journal’s courage in publishing articles
that critique the performance of organisations and institutions.2–4

However, the MJA’s reporting
of its own performance could be improved. For a decade, the Journal has reported the number of manuscripts submitted in each article category, the percentage
of manuscripts accepted, and the average time to acceptance or rejection for all articles and research articles.

As important as the time to acceptance or rejection is the time
to print or online publication for accepted articles. It is the raison d’être of a journal to disseminate knowledge. Such transfer takes place only when work can be read, criticised or built on by the medical community. A journal which accepts or rejects articles within 3 months and takes a further 9 months to publish arguably performs more poorly than one which takes 5 months to make a decision and 3 months to then publish. Knowing this publication metric is important for the MJA and potential authors
in the rapidly changing world of publishing. Online journals are becoming undeniably worthy competitors — 18 months ago PLOS Medicine overtook the BMJ as the fifth-ranked general medical journal by impact factor, and retained this position ahead of Annals of Internal Medicine in the latest rankings.5 The BMJ now publishes research article summaries in print issues, with full articles published online, allowing for more articles in each print issue.

It would also be ideal to report the time from initial MJA submission to decision to send to peer review or reject. Interestingly, the CMAJ uses this metric as a “service standard”.6 Finally, consistent with research and audit practice, some journals provide the range of times together with the mean to convey a full picture of performance.7

I urge the MJA to consider reporting the above metrics in the future and quantitatively surveying stakeholders on their views of the Journal’s strengths and weaknesses. Such data will provide important details that a crude “like” cannot, and thus help the MJA remain the region’s premier medical journal in its second century.

Better performance metrics for the MJA

In reply: Thank you for your endorsement of the MJA’s “likeability”. We agree that the total time from submission to online or print publication is an important consideration for intending authors and a meaningful journal metric. Currently, our manuscript submission system, which collates publishing statistics, does not have the capability to inform our team of the mean time from submission to publication or from acceptance to publication. However, we are in the process of transitioning to a new manuscript submission system that may have the capability to produce more detailed publishing statistics. Once this issue is addressed, we would be willing to report such statistics in the MJA, so that readers may assess for themselves the Journal’s performance.

We also agree that the gold standard in this area is to publish research articles online as soon as they are accepted and edited, with later allocation to a print issue. The MJA is moving towards this model.

Rapidity in the “first pass” decision to review or reject is an important service to authors. In the period 2011–2012, the average time to reject was 33 days. In the past 12 months, we have sought to address this issue by offering a rapid abstract assessment facility for full papers, and by implementing an initial “screen” of every manuscript by a Senior Deputy Editor within a few days of its receipt. We look forward to consequent improvement in this metric.

We welcome feedback from our stakeholders. If the MJA remains valued and adequately resourced, we believe we can indeed remain the region’s premier medical Journal and meet the standards set by our international colleagues.

Breathe deeply and say “ninety-nine”

A rich heritage and an optimistic future: the Journal’s new Editor-in-Chief contemplates its upcoming centenary

On 4 July 2014, the Medical Journal of Australia will celebrate its centenary; so we are about to turn 99. As we contemplate the approaching milestone, we hold our breath a little — a lot of batsmen wobble at 99!

Another significant date is also fast approaching. Whatever the outcome of the federal election on 14 September, new national policies for the financing, governance, quality and scope of publicly funded medical and hospital care will soon be under construction. For these policies to work well, the new government will need the participation of those who will implement them, including, quite obviously, the medical profession. For this participation to be at its best, the profession needs access to the information that underpins high-quality professional performance. Throughout its 99 years, the Journal has helped communicate that information among the profession and beyond.

My historian colleague Milton Lewis points out that in playing this role, the Journal has continued a tradition dating back even further — to colonial days. The first Australian medical journal was born in Sydney as early as 1846. Lacking adequate support, it soon ceased publication. But the better organised Victorian profession (has anything changed?) was able to establish the quarterly Australian Medical Journal in 1856.

The Australian Medical Journal continued to be published in Melbourne for over five decades until, along with the younger, Sydney-based Australasian Medical Gazette, it was replaced by the national publication, the Medical Journal of Australia.1 Throughout this time, the other significant source of intraprofessional unity (and an effective political player at both state and federal levels) was the British Medical Association, the first Australian branch of which was set up in Victoria in 1879 and the second in New South Wales the following year.1 Its successor, the Australian Medical Association, now operates the Journal.

The Journal has contributed to the development of medical and health care by providing a place where research and clinical observation are published; where thoughtful opinions based on experience and evidence from the sciences and practice are offered; where concerns — ethical, political and legal — about health and health care are raised; where life’s passage is marked (often with obituaries), successes are celebrated, and courage and outstanding professional service are recognised. The wit and wisdom of correspondents have entertained and stimulated, and the Journal has been a strong component of the professionalisation of medicine in Australia.

The Journal has regularly changed its format and livery, but its central purposes have remained largely intact. Now it is also available online — on mobile phones, laptops and (non-medicinal) tablets — anywhere, any time, as it joins the dance of the internet. The dynamism that is challenging print media more generally extends its challenge to the Journal. New business models to sustain it are essential, and work to develop them continues. But, for a near centenarian, it has shown remarkable flexibility, optimism and athleticism. If only we could all do as well at 99!

This is an excellent moment for the Journal to promote and strengthen the publication of research, especially that which assesses clinical effectiveness and new ways of organising and providing care. Policymakers, managers and clinical practitioners are hungry for evidence to help them decide.

As McKeon and colleagues noted in their recent review of health and medical research in Australia, we spend comparatively little on health care research and development.2 They call for a substantial increase in research and development investment (to 3%–4% of government health expenditure) to overcome the problem of expenditure on delivery of health and hospital care, which is rising faster than our willingness to pay. The Journal is here to publish and disseminate such research.

Medical journals depend heavily on voluntary contributions from doctors and other health service professionals, research workers, patients, politicians, health service managers and experts from diverse fields with an interest in health and medicine. Without the altruism of colleagues presenting their ideas for others to read and critically examine, there would be no journals. Along with professional advancement, the desire to share insights for the benefit of patients features strongly among the reasons why contributors write papers, commentaries, case studies and reviews. A love of the profession leads others to submit material that sustains the spirit, by way of personal stories, art, poetry or letters.

This is a rich background against which to plan for the future. The Journal takes these gifts, these contributions given to it in the past, and sees them as markers of both its heritage and future strength. They explain why we are optimistic and why we look forward to your company when we celebrate our 100th birthday in July 2014.

Honouring choices — life postmortem

A superb legacy is offered by a woman’s life cut short — her healthy organs

It’s no secret — I’m not surgically inclined. I generally find people’s insides unpleasant to see or handle.

More disquieting, surgical theatres depersonalise. When a person’s essence is reduced to a view of naked innards, neatly framed by sterile blue drapes, is it hostile to replace a cordial introductory handshake with a firm grip on their viscera? Although operations are consensual and intended to improve life, a thought lingers — who is the person on the operating table?

Even so, to a young intern, being invited to assist in theatre on my surgical rotation was a treat. Surgeons declare clinical convictions by steel blade, inflicting wounds to repair health. Such courage requires formidable confidence and arduous training. The surgeon’s reward is to command a theatre which, highly structured and intentionally austere, affords a protecting veil to facilitate their work.

Vocational chimeras, in each surgeon I perceive an architect, interior designer, builder, plumber and electrician of the human body. Their skill on display is impressive; time warps while dextrous hands renovate anatomy.

One day in the operating theatre, I met an exceptional patient — a healthy young woman, save for one quality. She was brain dead.

Long before we met, her healthy brain had formed a generous exit strategy for its fellow vital organs if the need arose — organ donation.

Twenty hours before we met, her brain had suffered the effects of a catastrophic subarachnoid haemorrhage. A transplant liaison team had been mobilised to support her anguished relatives, who then formed their verdict. Five hours before we met, the woman’s decision to donate her liver, kidneys, heart and lungs had been honoured. Thus an elaborate system was activated.

A liver transplant surgeon from another tertiary hospital arrived to procure the patient’s abdominal organs. Contrary to my fanciful surmise, he caught a taxi and not a helicopter. Unassuming entrance complete, the surgeon enlisted the day’s on-call surgical assistant — my senior resident.

Until then, our morning had been unremarkable. Postoperative patients were stable in the wards, the day’s tasks were already accomplished and the cricket attracted a growing audience around the television in the residents’ quarters.

Fascinated by the rare prospect of organ retrieval, I went to theatre and asked to observe. Enthusiastic and sporting full-length white overalls, the surgeon beamed. “You’ll never see anything like this, please scrub in and assist us.”

Few experiences in life wholly draw you into a situation, distort sensory coordination and tantalise your mind. As I scrubbed up, adrenaline coursed through me, and continued to do so long after the final suture.

Surgery is pre-eminent among medical fields regarding efficiency and outcomes — surgeons definitively thwart disease and injury with a scalpel. In this case, one life’s end would save five other lives.

When I assist in operations on the abdomen, I am usually underwhelmed by its organs. The liver, despite its essential functions, is aesthetically uninteresting and doesn’t even pulsate. Nor do kidneys. Bowels have the visual advantage of spontaneous activity, albeit reminiscent of the seething of primordial annelids. Overall, the abdominal cavity and retroperitoneal space display a menu of visually unexciting offal.

This patient’s abdominal contents briefly inspired a new level of interest as the surgeon established visual and tactile confirmation that they were free of overt disease. Satisfied, he prepared the liver and kidneys, and positioned ligatures behind major vessels.

In the spirit of team enterprise, he gained access to the thorax for the cardiothoracic surgeons. Witnessing my first median sternotomy, I saw the buzzing saw easily split the sternum then wax smeared on raw bone edges to halt bleeding. Thorax, prized open, revealed its jewel.

Her heart on debut to the external world, its beat revealed, fleetingly stopped my own.

Immediately the other viscera were demoted to their previous status. The shifting gleam of theatre lights reflected on her pericardium, as myocardium squeezed then eased, unhurried, beat after diligent beat. It compelled my fingertips to feel it fill, clench, hover and then quiver to reposition. Reluctantly, having no business in touching her heart, I resisted but my fingers yearned. Behind my right shoulder, abdominal preparations continued but faded from focus.

Oblivious to its exposure, resolute, her heart forced blood through passive bodily circuits with each contraction.

Existentially, the heart must coexist — other organs are essential to maintain homoeostasis, yet they are subordinate. Lungs require mechanical ventilation when the brainstem dies or when muscle and nerve function are disrupted. All organs require adequate perfusion. And all these things depend on a functioning heart, which beats without instruction.

The liver transplant surgeon stepped back when the cardiothoracic team arrived so I could get a better view. “I’ve seen a hundred”, he explained, “you should see this”.

Our patient’s tawny lungs, bearing the speckled carbon emblem of city living, were inflated and deflated by the anaesthetists, on request. Inspected and palpated by surgeons, they easily met requirements.

Her heart was scrutinised. Transplant liaison held a phone to the ear of the cardiothoracic surgeon, who confirmed to an interstate counterpart that “it’s a good little heart; definitely suitable”.

Everyone was poised, especially the patient. Cardioplegia was coordinated by the anaesthetic and cardiothoracic teams. Blood was replaced by chilled transplant medium and, inevitably, her heart began to falter. So did mine. Finally, when the great vessel cannulas bled clear, her heart arrested.

Respectful silence descended on the theatre, as redundant monitors were switched off and conversation diminished to essential communication.

Precious organs were transferred, carefully wrapped, to their crushed-ice baths. Clear plastic bags formed an interim sheath for transport, in the darkness of an esky, to distant recipients.

Not technically required that day, I was privileged to attend this woman’s intimate terminal event. Subspecialty surgical, medical and nursing staff converged with a grieving family to honour a dying woman’s wish.

Rescued from death, her organs survived to sustain the lives of other people.

In elegant solitude, her beating heart was a steady reminder that life is tenacious, right to the end. And evidence that sometimes, with breathtaking resolve, life defies mortality.

Note: Clinical details have been altered to protect patient and family privacy. Publication
has been approved by The Alfred Hospital Chief Legal Counsel and the Medical Director of
Organ and Tissue Donation, DonateLife Victoria.