Lab-testing of animals on the rise in Singapore

Push to be biomedical hub spurs growth, but strict rules are in place
Shobana Kesava, Straits Times 3 Jan 09;

ABOUT 250,000 research animals were euthanised here last year.

Used to test drugs, vaccines and surgical techniques, such animals are considered part of a critical step in the long and expensive process of approving a new treatment or medicine for human use.

Singapore is home to 24 licensed research facilities housing hundreds of thousands of animals. According to the Agri-Food and Veterinary Authority (AVA), mainly rats, mice and fish are used in experiments. Rabbits, dogs, pigs and monkeys also feature in some.

Most are euthanised at the end of a trial, which usually lasts days. But if they are approved for use in more than one project where there is little or no pain, it could be years.

Local research labs follow 'best practices'
Straits Times 3 Jan 09;

LOCAL laboratory conditions are based on international best practices, according to Singapore's watchdog for animal research activities.

Professor Bernard Tan, chairman of the National Advisory Committee for Laboratory Animal Research (Naclar), said guidelines were set down in 2004 to ensure the proper treatment and use of animals for scientific purposes in Singapore.

These guidelines take into consideration relevant scientific, ethical and legal issues, he said.

They are based on tried-and-tested approaches in the United States, Canada, Australia and New Zealand.

Researchers, for instance, must undergo training in handling lab animals. They must also prove that they have checked all available alternatives, so they will use as few animals as possible.

Criticisms by groups like Britain's Royal Society for the Prevention of Cruelty to Animals and local non-profit group Animal Watch that Singapore's guidelines are too lax, and the system not transparent enough, are unfounded, said Prof Tan.

'Britain has reached a point where biomedical research has been affected because of animal rights groups which conduct protests and endanger researchers' lives,' he said.

'We do not want to go that route and prevent the advancement of medicine, although all has been done here to ensure the highest care for the animals,' he added.

In 2003, based on a request for public feedback, Animal Watch said it worked with international bodies before offering 90 pages of recommendations for Naclar's proposed 'Guidelines on the care and use of animals for scientific purposes'.

One of Animal Watch's recommendations was to change a rule that ensured animals would not lose 'a significant amount of body weight'. The group wanted the phrase changed to 'no more than 20 per cent of (the animal's) body weight'.

None of the suggestions was adopted by Naclar because 'too much detail would become crippling', explained Prof Tan.

With veterinarians in attendance at research facilities, he said, such specifics are unnecessary.

Vets are in short supply. Fewer than 30 of the 147 licensed vets in Singapore specialise in lab animals.

Vets are a must at all facilities, and vets or veterinary technicians they have trained are expected to conduct inspections daily.

'The vet knows how animals react, as well as when and how they must be best attended to, and we'll keep these guidelines in place, at least for a couple of years more, before we review this approach,' said Prof Tan.

Dr Leow Su Hua, head of laboratory animal welfare at the Agri-Food and Veterinary Authority, agreed.

'Timely veterinary expertise and intervention go a long way in preventing or minimising suffering in lab animals,' she said.

Scientists here said ethical standards in the treatment of research animals had improved over the last decade.

While spot checks are conducted by the authorities, labs are expected to police themselves, said researchers.

One local scientist, who declined to be named, said although vets had never inspected her mouse lab at the research centre Biopolis during her five years there, the training was stringent and she had been taught by technicians how to correctly hold and treat mice.

For example, in an earlier training at another facility, she had been taught wrongly to lift rodents by the scruff of their necks - considered painful for the animal. At Biopolis, she learnt to cup the palm of the hand over the mouse's body to pick it up and curl its tail around a finger to make it feel safe.

Another researcher recounted that four years ago, he watched as newborn piglets at a hospital research facility were cut open without an anaesthetic to harvest fresh cells from their pancreas. Today, it is compulsory to anaesthetise the animals.

Prof Tan admitted he was concerned about small labs that might not be able to afford hiring full-time vets and that corners might be cut. Singapore has 15 of these labs.

'Vets who want to do this work are in short supply, so we do allow labs to share vets,' he said.

Requests by The Straits Times to four animal research facilities for visits or photographs of animal labs were turned down.

These are the largest facilities at the Biopolis, under the Agency for Science Technology and Research, the National University of Singapore, SingHealth's Experimental Medicine Centre and Maccine, a privately run primate facility.

Reasons given ranged from decision-makers being on leave to concern for the animals' safety and avoiding negative publicity.

SHOBANA KESAVA

Their numbers are believed to have risen in recent years in tandem with the Government's decision to push biomedical research as a key pillar of growth.

Mice are the most commonly used animals. They are often used in cancer, genetic and stem cell research while primates like macaques may be used in vaccine and Alzheimer's studies and to research healing processes.

To make sure the creatures were treated in an ethical manner, the National Advisory Committee for Laboratory Animal Research (Naclar) was set up in 2003.

Its guidelines for the humane treatment of animals in laboratory research were made part of the Animals and Birds Act in November 2004. An errant scientist found treating a lab animal cruelly can be fined up to $10,000 and jailed for a year. None has been found flouting the law here so far.

Explaining the need for animal testing, Naclar chairman Bernard Tan said it was part of the process before international bodies like the United States Food and Drug Administration consider drugs and therapies for approval. Such testing was made compulsory in the Nuremberg Code, drawn up after Nazi doctors were tried for conducting scientific experiments on humans during World War II.

'Singapore needs to be seen as a professional place fit for the best research to be done here, and this includes making sure the standards of animal care are world class,' he said.

Each research organisation that has an animal facility now has an Institutional Animal Care and Use Committee (IACUC) comprising at least five people, including a scientist experienced in the use of animals, a lab animal veterinarian, a non-scientist such as an ethicist or lawyer and a representative not affiliated to the research organisation.

Their job is to determine if the scientific experiments proposed on animals are warranted, ethically conducted and reduced to the bare minimum to produce scientifically valid results.

In addition, the facilities of institutions like the National University of Singapore (NUS) and the Experimental Medicine Centre (where heart problems, healing and joint problems, among others, are studied), which doctors under the SingHealth group use, are internationally certified.

Pigs, because of their similar organ functions and responses to humans, are induced to have heart attacks, for example. They would then be treated with the researcher's proposed therapy or drug.

A heart stent for humans was developed at the facility this way.

SingHealth, NUS and the Agency for Science, Technology and Research (A*Star) all told The Straits Times that they had independent experts checking on their operations.

AVA's head of laboratory animal welfare, Dr Leow Su Hua, said a small team of AVA officers inspect all animal research facilities at least once a year, to ensure facilities comply with Naclar guidelines. 'There's a huge amount of documentation they need to put in place. During the audits, we examine this, tour the facilities and highlight any deficiencies observed for the facilities to rectify.'

All researchers also undergo 'stringent training' said chairman of A*Star's IACUC, Dr Sathivel Ponniah.

A*Star neurobiologist Gerald Udolph, who is on the committee, said this is made up of two days of theory and a day of practical sessions in the labs. 'There are very high standards here. Even overseas scientists come for the training by scientists with decades of experience from the US,' he said.

Singapore's standards are based on governing bodies of the US, Canada, Australia and New Zealand. Anything with a backbone, from fish to non-human primates, falls under the rules.

Researchers must prove the need to use animals at all. For example, to find out how a chemical would behave in cells, it could be placed in a petri dish with these cells grown from stem cells, instead of being injected into an animal.

Where animal use is unavoidable, they must show they have minimised their use to the committee, and get veterinary advice on how to limit the pain inflicted.

At NUS, zoologist Peter Ng, who is director of the Tropical Marine Science Institute, said his labs now get spot- checked 'all the time' and the difference in young scientists' attitudes from 10 years ago is stark. 'I used to find things like junior scientists keeping some of their lab rats in dingy conditions before they began their experiments,' he said.

Now they would have to be housed in clean cages with fresh bedding and enough room to run around. Some are provided tubes, tunnels or igloos to run through for enrichment.

They must also be euthanised humanely before any undue stress is caused.

Said Professor Udolph: 'If a tumour gets too big, there is no point allowing the mouse to suffer when we've already learnt the impact of the disease, for example.'

stlocal@sph.com.sg

WHY EAT MEAT THEN?

'Most Singaporeans are happy to eat all the meat they want and, on the flipside, they'll tell me scientists are evil, because we kill animals during research. Yet they want medical verification of products. This has to be done through testing on cells, followed by animals, then humans.'

Professor Peter Ng, director of the Tropical Marine Science Institute

POSITIVE CONTRIBUTION TO MANKIND

'Being a veterinarian at an animal research facility may not be as glamorous as working in a small animal practice, but it does make a positive contribution to animal welfare and mankind.'

Trained veterinarian Leow Su Hua, head of laboratory animal welfare at the Agri-Food and Veterinary Authority

RESTAURANT CONDITIONS WORSE

'You just need to visit restaurants where it is accepted that frogs, crabs and live fish are kept in crowded glass cages. Our animals are treated much better.'

Institutional Animal Care and Use Committee member Gerald Udolph. Up to five mice are allowed in one lab cage.

ALLEVIATING HUMAN SUFFERING

'It could take anything from 50 years to never to eliminate animal research, because we do not know the complexity of organisms' cells and tissues. At the end of it all, we want to alleviate human suffering; so if you want to quarrel with that, quarrel with that.'

Naclar's Prof Bernard Tan, on whether Singapore should look at cutting back on research using animals

LOOK FOR ALTERNATIVES

'We have never viewed lab facilities here, but we feel more funds and effort should be put into finding alternatives.'

Mr Louis Ng, executive director, Animal Concerns Research and Education Society

Striving to avoid the use of animals
Straits Times 3 Jan 09;

RESEARCH institutions around the world are investing in alternative methods to minimise the distress inflicted on animals when testing new medical treatments for humans.

They include the Johns Hopkins Centre for Alternatives to Animal Testing in the United States, and the European Centre for the Validation of Alternative Methods based in Italy.

Last year, the British non-governmental organisation Fund for the Replacement of Animals in Medical Experiments (Frame) spent close to $1million on finding research alternatives.

Viable methods published by such organisations must be applied in Singapore's research facilities before scientists resort to animal testing, according to local guidelines.

Animal testing includes inducing conditions ranging from diabetes, cancer, heart attacks and Aids in research animals and then trying out the effects of new drugs on them.

Some of the alternative methods include:

# Cellular studies: Tests to understand the behaviour of cells are carried out in a petri dish, instead of using animals.

# Computer modelling: Bioinformatics allows scientists to understand how dissections and injections should be done, as well as how cells, tissues and organs respond to stimulation by drugs or therapies.

# Genomics: The study of inherited traits from body fluids like blood.

# Stem cell research: Human cells may be grown into cells or organs with different functions, which can then be tested.

At the National University of Singapore, at least two animal-free testing methods have been developed.

One involves growing liver cells to test the toxicity of drugs for liver disease.

The other is a technology that keeps the horseshoe crab from being killed for its blood. The blood's clotting mechanism is used in the biomedical industry to identify harmful bacteria. This clotting factor has now been cloned and can be produced without the crab.

SHOBANA KESAVA

Guardian of lab animals' welfare
Bryan Ogden helps ensure top-quality care for subjects of medical testing and research
Shobana Kesava, Straits Times 3 Jan 08;

HE WAS called a young Dr Dolittle in his hometown in Minneapolis, in the United States, because he was already operating his own makeshift animal hospital as a child.

Dr Bryan Ogden, 55, fulfilled his dream of becoming a veterinarian, but switched from small animal practice to laboratory animal medicine 20 years ago. The director of veterinary services at primate breeding and research facility Maccine is in charge of over 1,000 monkeys used for research in Singapore, including those bred in Bintan, Indonesia. He tells The Straits Times why his work is important.

# What does your work involve?

I provide health care for animals used for research, making sure it is done humanely and in compliance with regulations and international ethical principles, using the best available science. I look into housing, feeding and water, and psychological well-being as well.

The animals are used in biomedical research to evaluate potential drugs that are meant to help improve human health. Pharmaceutical and biotechnology companies come to us to test their novel compounds in preparation for their safe and effective use in humans.

# Why did you choose this field?

The vet oath swears that we will use animal health and science for the benefit of animals, mankind and science. I feel I'm able to do all of those things.

I'm in a better position to make an impact now, because vets working in research make sure everything is done ethically and in compliance with regulations. We have oversight over all the care and use of the animals.

# How can making animals sick for the sake of human health be seen as being good for animals?

It does in fact benefit animals. Not necessarily the ones that have the research done on them, but every drug, every therapeutic, anaesthetic and pain-relieving medicine that we use has been tested first on animals, and then gone full circle, to be applied to animals in vet care. So it would benefit them ultimately. Vets can use any drug that is intended for humans.

# What backlash has there been in your career choice?

In the US, my colleagues have had mock car bombs placed under their cars, they've received razorblade letters in the mail and threats. Others have had windows broken and letters sent to all their neighbours to say an evil person is living in their midst.

It isn't like that here. People accept that we give the best care we can to the animals and understand that what we do benefits people. Regulations here are as strict as they are in the US.

# Why did you come to Singapore?

There's been animal research in Singapore for many years, just more carefully regulated since 2004. In August that year, I came here to try to help implement and enforce those guidelines with the help of the Agri-Food and Veterinary Authority.

I head Maccine's veterinary services and oversee work at the Singapore General Hospital. There is only one other veterinarian certified by the American College of Laboratory Animal Medicine in Singapore: Dr Patrick Sharp, who heads the National University of Singapore's lab animal research unit.

There's also a local, Dr Frederic Chua, with a special interest in aquatic animals, who consults for a number of clinical research organisations specialising mainly in fish and rodents.

# With 24 licensed facilities that have hundreds of labs, how can vets check on all scientists' work?

A lot of day-to-day work is done by trained technicians. They are supervised by licensed lab animal vets but they can function on their own on a daily basis. Singapore could do with two to three more certified vets.

# Maccine has a breeding facility in Indonesia. Is it the main supplier of primates to Singapore?

Less than 0.3 per cent of animals used in research are monkeys. Over 400 monkeys are used in Singapore by several licensed research facilities here.

Maccine is one of the main users. We do both breeding and research as a clinical research organisation.

We have scientists who collaborate with pharmaceutical companies to test drugs or compounds in biologics that the company wants to use on humans. But these have to be tested on animals first to meet international toxicology requirements.

# Singapore's National Advisory Committee for Laboratory Animal Research says top quality of care hinges on vets. What do you do to ensure this?

Every time there's surgery done - say to implant a device being tested, to put in catheters to take samples, or put in telemetric sensors which collect data from a transmitter in the body to measure the heart rate and body temperature and send it by radio signal to a receiver - there's careful choice of anaesthetics and post-operative care, with painkillers to prevent pain.

We control the quality of feed and water, and provide enrichment for species-typical behaviour.

Rodents get bedding material of cotton or paper which they can make into nests, monkeys get toys and we let them watch television.

We rotate videos to different rooms so they don't get bored. Tom & Jerry cartoons in Chinese is their favourite.

# Wouldn't vets paid by an organisation put the interest of the institution above welfare of animals?

The approval process for research programmes is extremely strict. It isn't the vet alone who makes decisions, although I believe in the integrity of my colleagues and that we have high value placed on animal welfare. The Singapore Association for Laboratory Animal Science offers training classes to ensure the highest level of best practice.

Each research group's institutional animal care and use committee must have a lab animal vet, a scientist, a non-scientist and one outside member not affiliated or related to anyone within the institute. It could be a member of the clergy, a retired science teacher, an ethicist or a bench scientist who doesn't work with animals. Some understanding of science would help. In the US, some are from the Humane Society and I know of a Catholic priest who was one.

No research is done until the protocol is approved and all ethical issues addressed.

# What do you count as personal successes?

In 2000, my wife, who's allergic to peanuts, was exposed to them and went into anaphylactic shock. The university hospital in Oregon in the US was really close by so I rushed her over. She'd already stopped breathing but they were able to save her using emergency techniques that I had helped physicians learn as we'd done life support classes using pigs.

My job had been to anaesthetise the pigs, make sure they didn't have any discomfort during the whole procedure as the doctors put in catheters, chest tubes and conducted tracheostomies. Physicians who had taken that course saved my wife's life.

For years, I also worked with a team of cardiothoracic surgeons, nurses and perfusionists who performed heart and lung transplants in monkeys. They went on to apply that to humans.

And I was involved in the research that went into developing what is now one of the hottest cancer drugs, Gleevec, which has shown 90 per cent effectiveness in treating multiple myeloma - a cancer of the plasma cells.

It has revolutionised cancer therapy. And before Gleevec made it to humans, the drug first had to be tested on mice and then a large animal species.

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