Cancer patients testing drugs on mouse ‘avatars’
Scientists often test drugs in mice. Now some cancer patients are paying a private lab to breed mice that carry bits of their own tumours so treatments can be tried first on the customised rodents.
The idea is to see which drugs might work best on a specific person’s specific cancer. Studies can suggest a certain chemotherapy may help, but patients wonder whether it will work for them. Often there’s more than one choice, and if the first one fails, a patient may be too sick to try another, so hundreds of people have made “mouse avatars” over the last few years to test chemotherapies.
But there are no guarantees the mice will help. “There’s not a lot of science” to say how well this works, and it should be considered highly experimental, said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society.
There are some early encouraging reports, he said. One study of 70 patients found the mice generally reflected how well patients responded to various drugs. But there is no evidence that using mice is any better than care based on medical guidelines or the gene tests that many patients get now to help pick drugs.
Mouse testing costs $10,000 or more, and insurers don’t cover it. It takes several months, so patients usually have to start therapy before mouse results are in. “I do see promise, but it’s very time-consuming, it’s very expensive. For the average patient, standard care is going to be the way to go,” said Alana Welm, a cancer researcher at the Oklahoma Medical Research Foundation.
Several labs breed these mice but the main supplier to patients has been Champions Oncology, a company based in Hackensack, New Jersey, that also operates in London, Tel Aviv and Singapore. About 7,000 mice are kept in a Baltimore lab with 6 rooms that resemble stock rooms of a shoe store, with tall shelves that hold row upon row of plastic cages labelled with each cancer patient’s name.
Most mice are white-haired females, but others are hairless. Some live alone while others climb over one another and sleep in small piles. All have easy access to food and water, and many bear signs of the tumour graft — a shaved portion of hair, an incision scar and a lump growing off one side.
Patients have a tumour sample sent to Champions, which charges $1,500 to bank it, plus $2,500 for each drug tested in groups of mice implanted with bits of the tumour. Most patients try 3 to 5 drugs and spend $10,000 to $12,000, said Champions’ chief medical officer, Dr. Angela Davies. Mice have some drawbacks, said Dr. Benjamin Neel, director of research at Princess Margaret Cancer Centre in Toronto and a spokesman for the American Association for Cancer Research.
The tumour grafts are under the mouse skin — not in places where the cancer normally occurs, such as the pancreas or lungs, and therefore don’t reflect the human tumour’s environment. The mice also have highly impaired immune systems so they can tolerate the human tumours. That means they don’t reflect how a person’s immune system would respond to a treatment and cannot be used to test immunotherapies. “Even if it turns out these have real value,” they’re likely to be eclipsed by newer advances, such as ways to grow tumour cells in a lab dish that take only a few weeks, he said. It’s worth remembering that it has been proven that a majority of drugs known to work in humans are ineffective on human cancers implanted in mice.
Real alternative to animal testing
Fraunhofer Institute researchers have developed a promising alternative to using animals in experiments – a mini-organism inside a chip, which enables complex metabolic processes within the human body to be analysed realistically.
Researchers at the Dresden, Germany-based institute, working jointly with the Institute for Biotechnology at the Technical University (TU) of Berlin, say their solution could render the use of animal-based experiments superfluous in medical research because it faithfully replicates complex metabolic processes in the human body with startling accuracy.
‘Our system is a mini-organism on a 1:100,000 scale to the human being,’ says Frank Sonntag of the Fraunhofer Institute for Material and Beam Technology IWS. Human cells from various organs can be applied to several different positions within the chip.
The researchers obtained the cells from blood donations that were made available for research purposes. These ‘mini-organs’ are connected to each other through tiny canals. ‘This way we simulate human blood circulation,’ Sonntag explains.
Working much like the human heart, a micro-pump continuously transports liquid cell culture medium through infinitesimal micro-channels. The IWS researchers can modify the exact configuration of the chip, i.e. the number of mini-organs and the connection to the micro-channels, specifically to different sets of questions and different applications.
With the chip, it is possible to test both the active ingredients in new medicines, and also study cosmetics for their skin tolerability. The concept of combining various cell samples with fluid channels has been around for a long time, but this new system has 2 distinct advantages over previous approaches.
First, the microfluidic system is miniaturised and the pump is capable of channelling the tiniest flow rates of less than 0.5 microlitres per second through the channels. ‘This means the relationship between cell sample and liquid media is authentic,’ says Sonntag. If this ratio is incorrect, imprecise results will ensue. Second, the microfluidic system ensures that there is a constant flow of liquid cell culture medium. This is important, since some types of cells can only present ‘body-like’ morphology if they are stimulated by a current or flow.
To test the effect of a substance, the scientists initially loaded various cell samples onto the chip. Then the active ingredient to be tested was added through the medium for the cell sample of the organ into which the substance would be introduced in the real human body. For example, they could include the cells of the intestinal lining. The same metabolic responses are then processed on the chip just like in the human organism. ‘We use cell samples from various sexes and ethnicities.
We can set variations in body size and weight as desired on a scale of 1:100,000,’ says Sonntag. The scientists can see exactly which metabolic products form within specific cell samples, and what effects they might have on other cells. The results are ultimately even more predictive than those of animal-based experiments because the effects on the body of a mouse or a rat cannot be applied to human beings at a 1:1 ratio.
The artificial organism is already being used by scientists in the cosmetics industry. But, in addition to research on active ingredients, there is also another potential application. ‘We know today that certain kidney cells, the endothelial cells, play a key role in almost every kidney disease. With the in vitro tests to date, there was always the problem that the endothelial cells worked only under current conditions.
Here, our multi-organ chip could offer a test environment that would allow you to observe how cells regenerate following an injury,’ says Sonntag.
Training manual reveals cruelty
Scotland for Animals has obtained the internal training manual for animal experiments in Scottish research units.
Photographs show animals in highly distressing situations and many appear to have been taken within Glasgow University. SfA spokesman John Patrick: “This document is riddled with misinformation based on outdated ideas, it actively encourages bad practice. It’s worrying that this is the benchmark for medical research in Scotland”.
“The fact that this manual endorses brutal killing and restraint methods is a national embarrassment. It puts to rest the fallacy that animals are treated with care and respect in the UK vivisection industry”. “Scotland for Animals has called for jurisdiction over animal research to be included in any further transfer of powers to the Scottish Parliament.
We owe it to our families and everyone we care about to bin the use of animals and invest in real research”. Pictures show animals such as dogs, cats and rabbits being used in procedures. Dr Andre Menache, CEO of Antidote Europe: “The authors carefully chose to ignore the growing debate within the scientific community about the validity of animal experiments.
The authors claim that the main opposition to animal experiments comes from welfare groups. Why do they ignore the British Medical Journal?” “One of the photos in the manual shows how mice are restrained for taking blood samples from a vein in their hind leg – by being squashed into a centrifuge tube. The human equivalent would be to push a person into a drain pipe just wide enough for them to get into but that would not let them get out again without help.
This is a terrifying experience as anyone can tell you who has ever been in in a confined position like this.” “Some killing methods encouraged can lead to extreme animal suffering when performed incorrectly, either due to inexperience or bad practice by the researcher.
This is incompatible with the 3Rs principle of reducing animal suffering. It is a sad reflection on the UK animal research community that these forms of killing an animal should still be allowed in the 21st century.” The document also reveals that there could be only 24 Home Office inspectors supposedly enforcing welfare laws in the entire UK.
The manual can be viewed here: http://www.filedropper.com/scotlandforanimals
EU chemicals regulator scolded over animal testing
The European Ombudsman has upheld a complaint made by animal rights group PETA that the European Chemicals Agency (ECHA) is not doing enough to enforce substitution of animal testing when companies prepare safety data on compounds under EU regulations on registration, evaluation, authorisation and restriction of chemicals (REACH).
The ECHA’s triennial report on animal testing in June 2014 showed progress on alternative mechanisms for meeting REACH requirements without animal testing. However, the agency admitted that some firms had initiated animal tests that could have been substituted for validated in vitro methods, and that some animal tests were being undertaken without consultation with the ECHA as to whether they were necessary.
After negotiations, the ECHA has agreed to step up its enforcement, making better use of its existing powers. The regulator will also support executive bodies in EU member states in investigating cases where animal testing has been undertaken unnecessarily.
Full article: www.rsc.org/chemistryworld/2014/12/eu-chemicals-regulator-scolded-over-animal-testing
Brussels Airlines Stop Shipping Dogs and Cats!
Anti Dierproeven Coalitie (ADC) released footage of crates of cowering beagle dogs being transported from America to Belgium by Brussels Airlines for laboratory experiments.
In response, many animal protectors here in the UK supported ADC’s call for action by contacting the airline. After entering into talks with Brussels Airlines, the shipper has released a statement to ADC confirming an embargo has been placed on the shipping of dogs and cats for vivisection.
Animal abuse at Oklahoma university
The US Department of Agriculture has cited the University of Oklahoma for animal abuse, according to Bloomberg Business.
A recent report by the USDA claims a research lab at the university exposed young baboons to hypothermia and housed the monkeys in unsafe, grime-filled cages. The Jan 25th report, obtained by Bloomberg, found the monkeys had been hosed down with cold water, and their cages contained “an excessive build up of grime, debris, and excreta on the bars.”
The report also says the lab staff were ill-equipped to care for the 12 baboons, including ones as young as 3 months old, who were placed under their supervision.
This is far from the university’s first citation for animal abuse. According to Bloomberg, the institution has been cited for animal abuse 16 times over the course of just 2 years.
In 2013, the USDA reported OU was euthanising dogs by electrocution using a 9-volt battery and failing to administer painkillers to dogs about to undergo surgery.
In an email statement to Bloomberg, VP of research James Tomasek said, “The University of Oklahoma takes seriously its obligation to comply with all federal and regulatory standards related to animal welfare.”
Moves to reduce animal use
(UK) Sheffield MP Clive Betts has backed recent advances to reduce the use of animals in laboratories.
The British Union for the Abolition of Vivisection, which campaigns to end animal experiments, has called for an end to the use of animal testing for household products such as washing-up liquid. BUAV has been campaigning against animal testing for more than 100 years.
The campaigns have been accepted in principle by the Government, which last year promised to implement the changes before the 2015 general election. However, with just 2 months until voters go to the polls, Mr Betts, Labour MP for Sheffield South East, has joined 83 colleagues in supporting a motion calling for immediate action.
Mr Betts said: “The Labour Government banned animal experiments to test cosmetics and its now time for this Government to ban tests for household products. “Many retailers now have own brands which don’t rely on animal testing, so there is no reason why legislation should not be passed to ban tests altogether.”
Michelle Thew, of BUAV, said: “We welcome support from Mr Betts for this motion.” Details of experiments that use animals are published on the Home Office website.
A spokesman for Understanding Animal Research said the development of alternatives for household testing meant there was a sharp drop-off from 2002 and there have been no such tests in recent years. Therefore, he added, animals would not usually be used to test products such as washing up liquid or toilet cleaner today.
New method validated
The European Joint Research Centre has validated and recommended a new method which is not based on animal testing, to identify chemicals that can trigger skin allergies, estimated to affect already 20% of the population in Europe.
The human Cell Line Activation Test (h-CLAT) has been developed by industry and validated by the JRC managed European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM). It will help the identification of chemicals that can lead to allergic contact dermatitis (ACD), one of the most common occupational diseases, and therefore allow the number of animals currently used for this purpose to be reduced.
So far the potential of chemicals to induce skin allergies was tested on mice and guinea-pigs. Following the validation process ECVAM now recommends the use of h-CLAT in the context of integrated approaches to testing and assessment, i.e. together with data from other non-animal methods and computer model (in silico) predictions.
The recommendation aims to inform scientific discussions at OECD in view of developing an OECD Test Guideline on the h-CLAT. The OECD Test Guidelines are internationally agreed test methods used by government, industry and independent laboratories. They are used to determine the safety of chemicals and chemical preparations, including pesticides and industrial chemicals.
CRUK and animal experiments
Furless mice injected with human cancer cells; Rats chemically poisoned for 6 months; Mice genetically modified to develop cancer.
Cancer Research UK (CRUK) has been criticised by Animal Aid for helping to fund a series of ‘crude and archaic’ animal experiments that were conducted at Edinburgh University. The experiments, which were investigating treatments for bile duct cancer, involved injecting genetically modified (GM) mice with human cancer cells, while other groups of rodents were forced to endure around 6 months of chemical poisoning to induce cancer.
Campaigners have accused CRUK of using clumsy and outdated methods that have been widely criticised in the scientific literature. One of the CRUK-supported experiments used ‘nude mice’ – furless rodents who have been genetically modified to suffer from a weakened immune system.
These mice were injected with human cancer cells, and made to endure the growth of a tumour inside them for 3 weeks before some of them were given treatments to reduce its severity.
Another experiment used a different group of GM mice, who had been engineered to develop cancer when subjected to around 6 months of chemical poisoning. The chemical used was thioacetamide (TAA) – a substance that has traditionally been employed by the leather and motor fuel industries.
A group of rats were subjected to the same disturbing poisoning regime. Animal Aid argues that the methods used are outdated as well as cruel. Injecting human cancer cells into mice has long been regarded as a highly unreliable means of predicting how humans will respond to treatments.
Unlike the mice used in such research, human cancer patients have a functioning immune system, and this has a significant impact on the course of the disease. Even CRUK appears to have little faith in this method of research, declaring in a promotional poster that ‘the time for reliance on such models to determine the response to a new therapy has passed’.
Animal Aid is similarly critical of the practice of genetically modifying mice or poisoning rats in an attempt to ‘model’ bile duct cancer. Altering one or 2 genes in mice, argues the group, is a reductionist, simplistic approach, since human cancers are usually caused by multiple mutations in co-existent cells, and depend on a highly individualised cellular environment.
Poisoning rodents has, unsurprisingly, repeatedly failed to generate progress in the treatment of bile duct cancer. Treatments that appeared successful in these tests, such as sorafenib, have had to be withdrawn from clinical trials for bile duct cancer.
After all, humans do not develop this type of cancer by being forced to ingest a chemical from the leather industry. CRUK has serious questions to answer about how it decides which research to fund. In 2013-14, CRUK had a fundraising income of £490m. It has a duty to its dedicated fundraisers and donors, not to mention the victims of cancer, to ensure that this money is spent on research that has a genuine chance of contributing to medical progress.’
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