Designing a killer to kill a killer

Unlike normal cells in our body, cancer cells keep on dividing and proliferating without control, forming lumps called tumours. If we find methods to stop such unrestricted growth, we can treat and cure cancer. Anti-cancer drugs are still not specific enough and often damage normal, healthy cells as well, leading to unpleasant side-effects. They also are not able to penetrate the tumour. ‘Surgical Strike’ or cutting off the tumour is not specific enough and tends to damage normal tissues as well. Physical tools such as nanoparticles, coated with ‘magic bullets’, which seek and destroy specific components of cancer cells, are limited by penetrability, clearance from the body after delivery and so forth. What is needed is a killer device that can open up the target cell mass and finish it off, and do so only on cancer cells and not harm healthy ones in the body.

Way back in 1893, Dr William Covey of New York thought up the unusual idea of using whole bacteria (or their extracts) for treating cancer. The argument is this: after all, these microbes enter our cells and wreak damage. He made extracts of microbes such as Mycobacterium bovis (one that causes TB in cattle) and found that tumours actually shrank in size upon treating with such ‘Covey toxins’.

Taming the shrew

This approach is, in effect, the use of one type of killer cells (microbes which cause disease to normal healthy cells, even death, if left untreated) to kill another type of killer cells (cancer). The trouble here is while they kill cancer cells, they may also damage healthy cells of the body; treating the body against such infection allows the cancer to come back. If only we find ways to ‘tame’ such microbes that they do not cause harm to normal cells, but specifically target cancer cells, we may have a winning strategy. While Covey could not do this, we now have ways to do so, thanks to the advances in genetic engineering, molecular and cell biology. The field of using bacterial cells, loaded with anti-cancer molecules, to fight cancer has grown fast in the last 20 years. The killer bacterium chosen by many researchers in the field is Salmonella typhimurium (the one that causes typhoid-like disease in rats, and leads to gastric problems and diarrhea in humans). The molecular biology of this pathogen (let us abbreviate its name as ST) is now well known, and genetically manipulating it is not difficult. A group of researchers at Yale University, Connecticut, USA, found that if we delete the gene called msbB from its genome, its toxicity towards normal cells is vastly reduced. However, although safe, the injection of this gene-deleted strain did not show substantial anti-tumour activity.

The group soon realised that compared to normal cells, tumour cells are far richer in ATP, the energy currency molecule in cells. Given this, if one were to delete the gene called purL (which codes for making the ‘A’ part in ‘ATP’) from ST, the modified strain would need external addition of ATP in order to multiply and grow. And the abundant levels of ATP are the teaser. Thus the purl- deleted ST strain would make a beeline towards the tumour cells, ignoring normal healthy ones. We thus have a second way of herding ST towards cancers.

What if we make a double mutant, that is, generate ST with both the msbB and purL genes deleted, grow and unleash it into the organ afflicted with cancer? This was indeed done about 15 years ago by a group of scientists from the pharmaceutical company called VION, near Yale University. This double mutant strain, termed V20009, was tried against mice with melanomas, and also on mice carrying human tumours grafted on to them. Intravenous injection of VNP20009 inhibited tumour growth anywhere between 57-95%. Plus, only live bacteria showed the anti-tumour effect, meaning that continuous infection by live bacteria is needed to eliminate tumours, and extracts or drugs with limited doses will not do. About the same time, a group from the National Cancer Institute, near Washington, DC, used VNP20009 to treat 24 human patients with secondary skin cancers and found it sufficiently safe for human use.

Making a package deal

Dr. Ravi Bellamkonda of Duke University, Durham, NC, USA went one step further, and decided to use VNP20009 as a carrier or vehicle, and loaded it with the protein called p53 which suppresses tumour growth, and another molecule called azurin which kills cancer cells, and also protects p53 from degradation. That such a twinning of p53 and azurin is useful was earlier shown by Dr. Ananda Chakrabarty of the University of Illinois College of medicine at Chicago.

Dr. Bellamkonda injected this cargo-laden ST on to rats which carried grafts of cancerous brain tumours obtained from humans. This therapy allowed the cancer-bearing rats survive for more than 100 days, compared with barely 26 days for untreated rats.

The beauty in using such cargo-laden double mutant pathogens is that (1) normal and healthy body cells are not affected, (2) they penetrate the body of the cancer cells, (3) this allows delivery of the drugs into the interior of the cancer cell (where conventional drugs find hard to enter), and (4) we can add more cargo, and allow additional cancer-killer drugs while keeping normal cells safe enough.

dbala@lvpei.org

File report on resident doctors’ working conditions: HC to Maharashtra

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The Bombay High Court today directed the Maharashtra government to file a report on the working conditions of resident doctors in state-run hospitals and medical colleges, days after their strike against repeated incidents of assault on them.

After looking at photographs of some government hospitals, a division bench headed by Chief Justice Manjula Chellur said, “This shows that overall conditions are deplorable.”

The bench asked the state government to file a report on working conditions of doctors at B J Medical College in Pune, Government Medical Colleges in Miraj and Ambejogai in Beed, and J J hospital in Mumbai.

The bench also asked the state to inform it about the steps it has taken to improve or rectify the situation.

The bench was hearing a petition filed by activist Afaq Mandaviya seeking action against doctors, who had gone on mass leave last week to protest attacks on them.

Nearly 4,000 resident doctors across Maharashtra had stayed away from work for several days since March 20, demanding enhanced security in the wake of a string of attacks on doctors by patients’ relatives.

They had called off their stir five days later following an ultimatum by the Bombay High Court and Chief Minister Devendra Fadnavis.

The Maharashtra Association of Resident Doctors (MARD) today informed the court that doctors, who abstained from duty last week, had resumed work.

The HC had earlier directed the doctors to resume work immediately and hoped that their demands would be settled amicably with the state government.

The state’s Advocate General Rohit Deo had informed the HC last week that the government has decided to deploy an additional 1,100 armed police personnel from Maharashtra State Security Corporation at all the state and civic-run hospitals.

“The first lot of 500 police personnel will be deployed at hospitals in Mumbai on April 5, while the remaining 600 will be deployed at hospitals across the state by April 30. This will be in addition to the already deployed policemen at the hospitals,” Deo had said.

The petition was posted for further hearing after two weeks.

A doctor’s life: Overworked and disillusioned, resident doctors are fast losing hope

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Overworked and disillusioned, resident doctors are fast losing hope, which in turn could spell the death knell for India’s rickety public healthcare system

It is 6 am and Arvind*, a second-year paediatric resident doctor at Mumbai’s KEM hospital has just woken up. The workday will soon begin. The only problem is he has no clue how long it will be — it could go up to as much as 36 hours.

For starters, from 8 am to around 12.30 pm, he will examine patients at the hospital’s Out Patient Department (OPD), which gets more than 800 of them on a daily basis.

Next, those patients who need to be admitted will have to be attended to. 2 pm onwards, he will have to man the emergency ward, which in any case is always teeming with patients.

On the days that Arvind is ‘on call’, his shift will end only after 12 noon the next day.

“There are times we sleep on the stretchers in the operation theatres. We carry our brushes with us. Returning to our rooms is a luxury on most days,” he says.

But that is better than sleeping during surgeries because that happens, too. “That is the only time we are not disturbed for extended period of an hour or two,” said another resident doctor on condition of anonymity.

Ironically, the few days that post-graduate medical students — or residents — got a break from work was when they went on strike late last month to protest working conditions, particularly physical attacks against them, usually by relatives of patients.

Brickbats, not bouquets

Late in March, the public healthcare system in Maharashtra and, briefly, in Delhi, came to a crashing halt when resident doctors took leave en masse to protest a string of attacks against their peers in other parts of the state.

The provocation was the brutal beating of Dr Rohan Mhamunkar, 31, in Dhule’s Government Medical College after an altercation with relatives of a patient; the resident, an orthopaedic doctor, he was beaten to within an inch of his life, and is likely to lose vision in one eye.

The incident led Maharashtra’s 4,500 resident doctors to go on mass leave till they felt secure enough to work, even as reports of more attacks against doctors poured in.

Soon, the Indian Medical Association (IMA), with 40,000 doctors as members — many of them former resident doctors — joined the agitation, which ended only after assurances from both Maharashtra’s Chief Minister Devendra Fadnavis as well as the Bombay High Court, and promises of a 1,100-strong security force for public hospitals.

But despite the imminent danger to their lives in the line of duty, the resident doctors became instant villains for making poor patients suffer. But that is only part of the story. After all, violence at the hands of frenzied relatives of patients is only of the many problems residents must face.

One for all, none for one

A resident’s travails start with the abysmal doctor-patient ration, sometimes as high as 1:200 during peak hours in some wards. “Most paediatric patients are accompanied by four to five relatives,” Arvind points out. It’s a ratio that has the doctors not just outnumbered but scared for their safety should things not go the way the families want.

The patients are often the poorest of the poor, who have no option but the country’s almost free, if doddering, public healthcare system. The resident doctors are here after having cleared a rigorous entrance test, beating thousands of competitors.

Patients coming to the tertiary hospitals like the KEM or Sion hospital are often from far flung areas, usually exhausted by the effort of accessing some sort of healthcare. The overworked doctors, too, have little patience left to focus on communication. It is an incendiary combination.

“Everyone thinks doctors are their slaves. Educated citizens and journalists are questioning us. What people are not trying to understand is that it is the government that has failed to deliver,” said Richa*, a second year resident doctor at KEM.

Multi-tasking machines

During her endless shifts, Richa does more than just attend to patients. She fills forms for the patients, many of whom are unlettered, fetches test results, and even shifts patients around for an X-Ray or a CT scan — all jobs that ward boys are supposed to do.

“On a good day a ward brimming with over 100 patients will have one senior nurse, one junior nurse and one ward boy, provided no one is on leave,” Richa* shares.

The acute shortage of ancillary staff is wearing down doctors.

‘On call’ days are the worst. It means that the resident doctor has to be available through the night. On such days the work stretches up to 36 hours and every resident doctors is ‘on call’ at least once a week in most hospitals.

At peripheral hospitals grappling with shortage of doctors though the number could be as high as 3 times in a single week.

And the room that they retire to, if they ever have the opportunity, is anything but welcoming. Four to five residents in the first year are often cramped in a 100 sq-feet room.

“There are times when the first year students don’t get a room till seniors vacate it in which case they have to share a side room near a hospital ward. Eight to nine residents occupy it at a stretch at times,” another resident doctor from KEM said.

In critical condition

Depression, too, is widespread. “We leave our personal lives behind us at 18. My mother wants me to get married but where is the time? Unless you find someone who is also a doctor, it is almost impossible to manage,” says Richa. Yes, they are willing to serve the patients but don’t they deserve a shot at a normal life, most ask.

Arvind says almost everyone in his family is a doctor — 30 in all — working across the world. “But they don’t have lives like these,” he points out. Not surprisingly, he is waiting to get out of the public healthcare system once he clears his residency.

And therein lies a huge problem. The system is so gruelling that the best leave the first chance they get.

Dr Aadil Chagla, neurosurgeon, KEM hospital, while clarifying that he does not believe in strikes, sympathises with the residents.

“The hospitals are far from clean and that also means that the people at the end of the food chain suffer the most. One must realise that the condition of the resident medical doctors is abysmal.”

Dr Girish Sawant, a gynaecologist who now works in the private sector, has horror-inducing memories. “When I interned at KEM one decade back there would be 60 patients in a ward and three to four resident doctors would be waging a war.”

“If we continue to be so apathetic then it will only lead to the downfall of our health care system,” asks Dr Pranali Ahale, gynaecologist at the Jogeshwari Trauma Care Hospital.

And yet, amidst the bleakness, the lack of a personal life, poor compensation and being treated badly, there are the occasional moments of light. As Richa explains: “When someone gets better and even acknowledges our effort, it makes up for all the hard work.”

(*Names have been changed to protect identity)

NEED TO KNOW

  • How long is the course: 36 months
  • How much do they make: Around 40,000
  • MBBS course: 5.5 years
  • Preparation for PG entrance: 1-3 years
  • Post Graduation (MD/MS): 3 years
  • 1-year compulsory service in government hospital
  • A year of preparation for super-speciality
  • MCH/DM: 3 years

Health ministry nod for more MD seats

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The Union health ministry has approved the addition of 184 postgraduate seats across nine government medical colleges in Bengal as part of a nationwide exercise to add more than 4,000 medical PG seats this year.

A health ministry order released yesterday lists over 1,900 additional MD and MS seats at over 100 government medical colleges across the country from the academic year 2017-18.

The remaining 2,100 additional PG seats will be in diploma courses.

Burdwan Medical College will be able to offer 45 additional seats, the highest among the colleges in Bengal.

The expansion will also mean 64 additional MD and MS seats in five medical colleges in Bihar, 99 in four colleges in Assam, and nine at the Rajendra Institute of Medical Sciences, Ranchi.

India’s 470-odd medical colleges currently offer about 64,000 undergraduate (MBBS) seats but only about 32,000 PG seats, of which some 18,000 are in the clinical subjects. The gulf between the numbers of MBBS and PG seats has meant intense competition at the PG entrance exams.

Health officials say the expansion of PG seats was made possible by changing the sanctioned professor-to-PG student ratio in medical colleges from 1:2 to 1:3. The move is expected to substantially increase the number of specialists available for health-care services in the public and private sectors.

The additional PG seats may also help build faculty at the district hospitals that are set to be upgraded into medical colleges from the academic year 2019-20.

In Bengal, the district hospitals in Birbhum, Cooch Behar, Purulia, North Dinajpur and South 24-Parganas have been selected for upgrades to medical colleges.

Anaesthesiology is among the clinical subjects allowed the highest number of additional PG seats. The Vardhman Mahavir Medical College and Safdarjung Hospital in New Delhi alone is set to increase its intake for the MD anaesthesiology course by 54 seats, from 11 to 65.

“Anaesthesiologists are needed in every surgery. They also manage patients in intensive care and patients in pain, and assist in palliative care. And there’s an acute shortage of specialists,” said a senior faculty member at the Indira Gandhi Institute of Medical Sciences, Patna, which has added 13 MD anaesthesiology seats.

A senior health official said it was easier to add seats for courses such as MD anaesthesiology and MD radio-diagnosis because, unlike most other specialities, they were not tagged to patient or bed requirements.

The faculty member at the Indira Gandhi Institute, who requested not to be named, said the increase in PG seats would also over time help ease the shortage of specialists at public hospitals in the districts.

“While many will work in the cities, we expect that some will also serve in small towns,” the faculty member said.

Entry to PG courses in both government and private medical colleges is determined by a centralised common test that the health ministry says has made the admission process “transparent”.