A University of Toronto scientist has discovered a family of hormones that have the potential to create medications to treat anxiety disorders. ZOE CORMIER reports
If “we have nothing to fear but fear itself‚” what would happen if we could eliminate fear itself? Research being done at the University of Toronto suggests that this might actually be possible.
Neurophysiologist David Lovejoy and his colleagues have discovered a family of four hormones‚ called teneurin C terminal associated peptides (TCAPs)‚ that have shown in tests to lower anxiety‚ fear and stress in mice.
These hormones are also found in the human body‚ but Dr. Lovejoy has not yet reached the stage where he can experiment on people.
However‚ he already anticipates being able to use the hormones‚ which are produced in the brain’s master control centre‚ the hypothalamus‚ to create medications for the treatment of anxiety disorders.
Although Dr. Lovejoy and his fellow scientists are just beginning to understand how TCAPs work normally‚ they have observed pronounced effects when the hormones are given in elevated doses.
When he gave rats daily injections of the hormones‚ they experienced a dramatic and long–term reduction in their “fear response.” For instance‚ when he tried to startle the TCAP–treated rats with a loud noise‚ “they didn’t really get stressed out‚” he says.
And when he gave TCAPs to hamsters‚ which normally run about eight kilometres a night‚ they “got on the wheel‚ kind of looked at it‚ and decided they didn’t feel like running‚” he says.
Conventional tranquillizers are also capable of sedating animals‚ so these results might not seem impressive. But‚ unlike tranquillizers‚ Dr. Lovejoy’s hormones can also make an animal more active.
For example‚ if you put a normal rat on a plank of wood‚ suspended from the ceiling with wires‚ with a box placed at one end that the animal can walk into‚ it will typically stay inside the box‚ avoiding the rest of the plank from which it could fall. But when Dr. Lovejoy treated rats with TCAPs‚ they comfortably explored around the edges.
This is the most curious thing about TCAPs: They have the ability‚ as Dr. Lovejoy puts it‚ to “normalize behaviour.” If you give the hormones to rats that are unusually hyperactive and sensitive‚ they will make them less active and sensitive to stimulation. But if you give them to animals that are unusually sedentary and unresponsive‚ they will become more active and sensitive.
Simply put‚ Dr. Lovejoy says‚ the hormones reduce anxiety.
These preliminary studies suggest the possibility of treatments for human emotional problems characterized by stress‚ fear and mood fluctuations‚ such as manic depression and anxiety disorders. Medications developed from these hormones would have a huge impact on a burgeoning health problem. According to Health Canada‚ anxiety disorders affect 12 per cent of the country’s population.
Dr. Lovejoy created a startup company a year ago to research commercial applications of his hormones‚ and he has just acquired financing. He is still in the process of finalizing the contracts‚ so at the moment all he can say is that “the funding is coming from a group of private American investors from Boston and San Diego.”
Originally from Winnipeg‚ Dr. Lovejoy‚ who received his PhD from the University of Victoria‚ began doing research on stress and anxiety at the Salk Institute in California‚ an establishment that has produced five Nobel Prize winners.
Dr. Lovejoy was working in the lab of Wylie Vale‚ who in 1981 made a landmark discovery when he identified one of the key stress hormones in mammals. This hormone‚ corticotropin releasing factor (CRF)‚ is the first chemical released by the body during a stressful event‚ such as an attack.
The secretion of CRF prepares an animal for a “fight or flight” action by elevating the heart rate and blood sugar and creating sensations of anxiety and fear. Chronically high levels of CRF have since been linked in humans to anorexia nervosa‚ depression‚ anxiety disorders and drug abuse.
In 1995‚ Dr. Lovejoy helped Dr. Vale discover a hormone in mammals closely related to CRF‚ called urocortin‚ a finding that they reported in the journal Nature; CRF and urocortin have a similar structure‚ and do many of the same things in mammals.
That same year‚ Dr. Lovejoy took a faculty position at Britain’s University of Manchester‚ where he looked for hormones similar to CRF in non–mammals.
He focused on rainbow trout‚ which had already had many of its genes sequenced. He took the stretch of hamster DNA that codes for the urocortin hormone‚ and looked for any trout genes that resembled it.
The first thing he found was a trout version of urocortin.
The second thing he found was something entirely new‚ which at the time he did not examine closely.
In 2001‚ Dr. Lovejoy returned to Canada to join the department of zoology at the University of Toronto‚ not having yet fully realized the significance of this little stretch of DNA.
“I had only looked at it a couple of times. Then‚ I was at a conference‚ at a boring talk‚ actually‚ and I found myself drifting and thinking: ‘What projects do I have on the back burner? Well‚ I’ve got this [new gene]; I’ll look at that.’ So I came back‚ looked at the genetic sequence.”
He realized that the DNA coded for a hormone. But this hormone was clearly different from CRF and from urocortin: It belonged to an entirely different family.
“I saw that and thought‚ ‘Wow.’ My hair stood up. I thought‚ ‘This is too good to be true.’”
Dr. Lovejoy and his researchers decided to put the rest of their work on hold to focus on this discovery.
In the space of two years‚ they discovered that there are four similar TCAP hormones and that all four are found in humans‚ mice‚ chickens‚ frogs and fruit flies. To put this in perspective: The first key papers on the CRF family of hormones were published in 1955; urocortin was not discovered until 40 years later.
“The tools are just so good now‚” Dr. Lovejoy says. “All we had to do was take our sequence and put it into the genome databases. And because we knew how to compare molecules using an evolutionary approach‚ we found that this hormone existed all through the vertebrates.”
Although the completion of the genome projects has greatly facilitated scientific discovery‚ hormones are rarely discovered‚ especially in humans. To discover an entirely new family of hormones‚ one that is also found in our own species‚ is even more unusual.
What is particularly unique about the TCAPs compared with the other hormones related to CRF is their ability to lower anxiety and fear — CRF elevates anxiety and fear. This is completely novel‚ which made it difficult getting Dr. Lovejoy’s work recognized by mainstream science.
“We had an unknown hormone‚ with an unusual processing‚ and we were saying that it reduced anxiety in adults. It was just too much [for people to readily accept]‚” he says.
“[Our work] was rejected [by journals] time and time again; we spent three years trying to publish our work‚” he continues. “It was a new family of hormones. Well‚ most scientists think that families aren’t discovered‚ and they certainly aren’t discovered by little labs at U of T; they’re discovered by big Nobel Prize–winning labs.”
Originally their work on trout and rodent TCAPs was presented in one paper with an evolutionary comparison‚ which Prof. Lovejoy was unable to publish. It was only when he split his findings into two papers‚ one on trout and the other on rodents‚ that his work was accepted by a peer–reviewed journal. The first TCAP paper appeared in June‚ 2004‚ in General and Comparative Endocrinology.
With the research progressing‚ one question needs to be asked: Could one do anything sinister with anti–fear hormones?
“In fact‚ after seeing what the hormones did to mice‚ one of my first thoughts was: ‘Oh my God‚ they’ll be able to use this to create a race of fearless soldiers‚’ ” Dr. Lovejoy says.
But this fear will not deter him. “No matter what you discover‚ an evil mind can turn it to something bad. This is the problem with discovery. But when you come up with something like this‚ do you focus on the bad things‚ or do you focus on the good things?”