OET Reading C49

Researchers have come up with a new method to control brain cells in live animals using specially designed receptor proteins that respond to the drug varenicline. While drug-responsive receptors have been around for some time, the new incarnations, described today in Science, have been structurally optimised, as has the drug itself, to create a novel repertoire of precise and powerful chemo-genetic resources.

7.1 How do you describe the “repertoire of chemo-genetic resources” in the first paragraph?

1. They are expensive.
2. They are new.
3. They are rare.
4. They are not easily available.

7.2 What does the writer mean by “the new incarnations” in the first paragraph?

1. A new method to control brain cells in live animals.
2. Specially designed receptor proteins.
3. Varenicline.
4. Specially designed receptor proteins and the drug Varenicline.

7.3. According to the paragraph:

1. Some animals use specially designed receptor proteins.
2. All animals use specially designed receptor proteins.
3. The research was conducted in animals that use specially designed receptor proteins.
4. The research was conducted in animals for which specially designed receptor proteins were used.

7.4 According to the paragraph:

1. Only the receptor proteins are structurally optimised.
2. The drug varenicline and the receptor proteins are structurally optimised.
3. Only the drug varenicline is structurally optimised.
4. Structural optimization described in this paragraph is a natural process.

The book was sent to nurses who are preparing for OET.
The book was sent to nurses so that they could prepare for OET.

7.5 What developments of drug-responsive receptors are reported in the first paragraph?

1. Drug-responsive receptors have been tested on live animals for the first time.
2. Some proteins have been found to be resistant to drug-responsive receptors.
3. The chemo-genetic resources have been extensively catalogued.
4. Both the drugs and the receptors have been enhanced.

“It really is an exciting new development that has great potential not only for basic research but potentially also in translation and applications for human use,” says neuroscientist Dr Christian Lüscher of the University of Geneva who was not involved with the research. “There is a tremendous need for novel medications that have higher selectivity and higher potency at very low doses, and hence fewer side effects. And this technology potentially fits these needs,” adds Dr Lüscher.

8.2 What is Dr Christian Lüscher’s reaction to this new development?

1. He says this development is unlikely to yield positive results.
2. He is concerned about possible side effects.
3. He thinks it could be used to benefit people.
4. He claims that, if the correct receptors are not identified, this development cannot be used.

8.3 Dr Christian Lüscher is:

1. Doubtful about the expected outcome of the new treatment.
2. Excited about the volume of proven results from the new development.
3. Optimistic about more advancement in the new development.
4. Happy that he could contribute potentially to the new treatment.

The aim of chemo-genetic techniques is to enable researchers to activate or silence specific cell types at will. Applied typically to brain cell manipulations, the techniques employ specially designed receptors that only respond to particular ligands (drugs or molecules). Introducing the receptors into chosen cells thus allows drug-dependent control of those cells’ activities.

9. In the third paragraph, what is the aim of chemo-genetic techniques?

1. To increase brain cell production.
2. To allow scientists to switch cells on or off by using specific drugs.
3. To make brain cells resistant to particular ligands.
4. To respond to the need for more brain molecules.

One of the principal chemo-genetic systems, called Designer Receptors Exclusively Activated by Designer Drugs, or DREADDs for short, has limitations. For one thing, a commonly used DREADD activator, CNO, was recently found to transform into the drug clozapine, which has widespread effects in the brain. Moreover, DREADDs are based on G-protein coupled receptors (GPCRs), meaning they must associate with ion channels in the cell to have an effect. “So if the cell doesn’t express the [necessary ion] channel it will simply not work,” Lüscher says. Scott Sternson of the HHMI Janelia Research Campus and colleagues’ new system by contrast is based on fusion proteins consisting of an ion channel domain and a receptor domain — specifically that of the acetylcholine receptor. “They are in themselves already the effectors,” says Lüscher, meaning they can work in essentially any cell type regardless of the other ion channels present. “That’s a big advantage.”

10. What advantage does the new technique developed at the HHMI Research Campus offer?

1. It is more versatile than the DREADD system.
2. It does not require the presence of clozapine.
3. It can eliminate ion channels.
4. It can replicate on G-protein coupled receptors (GPCRs) more readily

Rather than making both a designer receptor and ligand straight away, Sternson’s team first focused on creating receptors that would respond to a given FDAapproved drug. “To use chemo-genetics therapeutically you’re going to have a gene therapy component, which is the receptor, and then you have a chemical component, which obviously is a small molecule drug, and that, from a practical standpoint, creates certain regulatory challenges” in terms of clinical testing, Sternson explains. Starting with an approved drug would thus more likely result in a system ripe for translation into, for example, therapies for pain or epilepsy.

11. Why did Sternson’s team use an FDA-approved drug?

1. The team were given samples of an FDA-approved drug to work with.
2. Only FDA-approved drugs were available.
3. It is against the law to use a non-FDA approved drug.
4. An existing medication would increase their chances of a successful outcome

To that end, the team screened an array of safe, well-tolerated, brain-entering drugs for their ability to interact with a variety of fusion receptors. Varenicline, an anti smoking drug, stood out as a strong candidate, explains Sternson. To maximise the effect of varenicline the investigators then studied the crystal structure of the drug receptor interaction and, with a great deal of educated tinkering and patience, tweaked the receptor until they produced optimised versions many times more responsive than the originals. Indeed, in cultured mouse neurons as well as in live mice and monkeys, doses of varenicline substantially lower than that normally required for the drug’s nicotine-substitution effect were able to induce or suppress the activity (depending on the ion channel domain spliced to the receptor) of cells presenting the optimised receptors.

12. What was the team able to achieve with varenicline?

1. They incorporated a new ion channel domain.
2. They made it possible to use it on animals.
3. They improved it.
4. They added a new crystalline structure

Sternson’s team has also tinkered with varenicline itself to make versions of the drug that interact with the optimised receptors more specifically, or that offer yet more potency. In mice, one of these varenicline variants, when used at a three-fold lower dose than the original drug, could just as effectively suppress the activity of neurons expressing the engineered receptor and alter the animals’ behaviour. This is important for future translation of the system to human use, says Lüscher. “If you can use such low doses of varenicline then I anticipate there should be minimal side effects.”

13. What additional result is described in the seventh paragraph?

1. Varenicline was produced which had fewer side effects.
2. Stronger versions of varenicline were made.
3. A version of varenicline was made that is three times less expensive.
4. A version was created that could engineer new behaviour receptors

While these varenicline variants, like the fusion receptors, are so far only for research purposes, “I am rather cautiously optimistic that this will change the landscape of our ability to use chemo-genetics in a way that has the potential to fairly quickly be applied in clinical contexts,” says neuroscientist Gordon Fishell of Harvard Medical School who was not part of the research team. “We’re getting to a point where we can hack the brain.”

14. What is Gordon Fishell’s opinion of this research?

1. It won’t be long until doctors can use this development to help their patients.
2. It is likely to remain as research for the foreseeable future.
3. It poses a danger as some may use this research to try to hack a brain.
4. Chemo-genetics is the future of clinical contexts.