ST. GEORGE — The barren northeast corner of Dammeron Valley is not the place where someone would think to find one of the most advanced medical labs in Utah. But if the chief of that lab has his way, the end of Alzheimer’s disease will begin there.

Dr. Gary Jones is not looking at creating a cure for the disease that wipes a person’s memory and cognitive functions leading to death. He’s aiming to create a pill that will keep people from getting Alzheimer’s in the first place.

At the same time, Jones doesn’t want to give anyone false hope. Since Alois Alzheimer first identified the disease in 1901, there have been many attempts to find a cure or treatment. All thus far have failed. 

“We knowingly took this project on regardless of the history of failures in this area of research. The statistical odds are this drug will not work,” Jones said.

At his Dammeron Valley lab, Jones is working to develop a small organic molecule that, in theory, keeps Alzheimer’s from degrading the pathways of the brain.

The work on developing the molecule is mostly done. Jones is now hoping to move on to human trials in a short time.

“We know that our drug’s mechanism does precisely what it should do to prevent this disease,” Jones said. “A properly designed clinical trial will prove this, and such a trial will likely require six years.” 

Jones will be presenting some of his findings in May at the American Society for Pharmacology and Experimental Therapeutics’ annual meeting in St. Louis.

Jones, 76, already has some medical milestones under his belt. When he came to Southern Utah in 1991, he became its first neurologist and is one of the few neurologists in Utah to be named as a fellow of the American Academy of Neurology.

He implemented the protocol in St. George to treat patients with tissue plasminogen activator (tPA), also known as alteplase, which breaks down blood clots. According to the Mayo Clinic, alteplase has “significantly” increased the chances of surviving a heart attack or stroke since its introduction in 1996. 

Alteplase is a synthetic protein designed to seek out and destroy the cause of heart attacks and stroke. Now, Jones has come out of retirement to develop a molecule that does the same to the cause of Alzheimer’s. 

Medical scientists still don’t fully understand all of the mechanisms that cause Alzheimer’s, though Jones said he thinks he may have cracked the code.

“I just recognize Alzheimer’s as a challenge. It’s a problem that needs to be fixed,” Jones told St. George News, reiterating that he is looking to stop it before it happens rather than cure it.

“I don’t compare with the strategies that have been employed so far in drug discovery. I think the failure to acknowledge that prevention is really key has already done harm.”

Finding the lab and inspiration

Without directions, it might be hard for someone to find Jones’ Hamit-Darwin-Freesh Inc., in a desolate, northeastern corner of Dammeron Valley. The unmarked, rectangular buildings might be mistaken for warehouses or industrial buildings. Camouflage vehicles parked around it add a clandestine feel of a secret military installation.

Jones says there’s nothing sinister. He is a longtime collector and preserver of military vehicles. He also rejects the term “secret lab.” He makes no secret about the work he is doing at Hamit-Darwin-Freesh; there just aren’t many who would think the place to ask about Alzheimer’s research would be on a small street five football fields away from state Route 18.

Painted white arrows lead from a small parking lot to a door marked “no entry” below a sign reading “Health Force One Neurology.” St. George News was granted access inside.

There is no mistaking that one is walking into a lab. There are beakers and flasks, evaporators and fermentors, freezers and heaters. The smell in the air lies somewhere between putrid and stale – including the unmistakable scents produced by lab mice. Large silver hoses along the roof lead to a filtering system in case any local residents were worried about anything leaking out. 

The walls are adorned with whiteboards with equations and chemical charts one might see on “The Big Bang Theory” or remember from their high school chemistry class. Freezers chilled by liquid nitrogen to minus 86 degrees are filled with cell cultures. Despite the location and the sense of a “secret lab,” there is some equipment inside that is found at only one other place in the state: The University of Utah. 

While the advancing age of his body makes walking around the lab more challenging these days, Jones said his mind is still firing on all cylinders. And he wants to use that mind to keep others from losing theirs.

“I’m 76. I could croak here in the lab,” Jones said. “But my health is good. Except for the bones and joints, right?”

Assisting Jones is Justin Leavitt, who was born and raised in Southern Utah before getting a doctorate in genetics and molecular biology from the University of Utah in 2016. Leavitt could be seen looking at the monitor of a ChemiDoc imaging system seeing a gel causing a breakdown of the kind of brain plaque seen in Alzheimer’s patients. He has the enthusiasm of a child showing off their latest “Minecraft” project. 

Even so, Leavitt is under no delusions that the images on his screen are a “eureka” moment.

“There’s been literally hundreds of very, very hopeful Alzheimer’s drug trials that haven’t resulted in a practical drug,” Leavitt said. “So, you know, it’s a little bit daunting.” 

Someone entering the lab might also realize Jones has a sentimentality for those who have influenced him. On the walls are old portraits of family members and those who mentored and inspired Jones. Walking through the lab, Jones eyes a picture of late St. George native Dixon Woodbury, who pioneered epilepsy research, and the late University of Utah researcher Lou Goodman whose “The Pharmacological Basis of Therapeutics” – otherwise known as the “Blue Bible” – is still a go-to pharmaceutical textbook. 

There’s also an image of his grandmother, who died of Alzheimer’s.

The name of Jones’ company itself comes from two of his most important inspirations: A pioneer in chemistry, and the chemistry bonds with his wife, Mary Freesh Jones. 

“The name Hamit-Darwin-Freesh is derived from a chemistry professor at Oregon State University that was very influential in my life. His name was Hamit Darwin Reese,” Jones said. “ I took his first and middle names to honor him, and since my wife’s name is Freesh I swapped the two because Freesh rhymes with Reese and it honors my wife.”

And Jones is hoping it is chemistry that will stop Alzheimer’s from tearing apart people and families.

Fixing the brain’s highway

As early as 1974, Jones was writing papers about the functions of proteins on the nervous system. Nearly 49 years later, he is hoping to find the key to locking up brain cells against Alzheimer’s.

To understand what Jones and his team are trying to accomplish, there are five terms to keep in mind: Amyloids, tau, microtubules, microglia and proteases. 

Amyloids are sticky proteins that like wet flour stick together and build into balls of gunk that can be toxic to cells and can develop in different parts of the body. Where they form in the body can create a traffic jam like the corner of Green Spring and Telegraph in Washington City. 

If they form in the heart, they can restrict blood flow with a condition called cardiac amyloidis. If they form in the kidney, they block the organ’s filtration system, causing kidney failure. 

If they form in the brain, they become the beta-amyloid plaque associated with dementia and Alzheimer’s. However, Jones and other medical scientists have been befuddled by the fact that having beta-amyloid plaque doesn’t always mean a person has Alzheimer’s. 

“We’re still hooked on the amyloid hypothesis. There is extremely poor correlation of plaque in the brain with Alzheimer’s,” Jones said. “You can see old people with a brain full of plaque, and they do not have Alzheimer’s. And then you can see a person with just a few plaques that has Alzheimer’s.”

Jones’ own detective work is examining another protein called tau. Tau are the building blocks of much of the nerve cells that make up the brain, including pathways between nerve cells called microtubules. If the information transmitted in the brain were cars, microtubules are Interstate 15. 

“Together they form microtubules, which are highways. They’re freeways,” Jones said. “They’re trafficking avenues by which the brain can move … proteins, enzymes, different products, large and small molecules to flow throughout the brain. 

According to the National Institute of Health (NIH), in Alzheimer’s disease, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons.

Jones and Leavitt think they’ve found a way to utilize a mechanism within brain cells to fight what can cause that breakdown of tau in the same way white blood cells kill infection and disease in the bloodstream.

“For a long time, people believed that the brain was immune privileged. And that there was basically no immune system really happening there,” Leavitt said. “And now we know that’s very untrue.”

Those cells, which according to Leavitt, function as the white blood cells of the brain, are called microglia. As defined by the National Institutes of Health, microglia are resident cells of the brain that regulate brain development, maintain neural networks and repair brain injury.

Jones and Leavitt say their work has shown microglia can be boosted to not only fight Alzheimer’s, but prevent it in the first place. 

“The microglia seems to be the most important cell type in Alzheimer’s disease, apart from the neurons,” Jones said. “The only role the neurons play, as far as I understand, they died.”

But microglia is only one prong of the attack being concocted in the Dammeron Valley lab. The other is a catalyst substance known as a protease. If the brain plaque were ghosts, protease is Pac-Man.

“A protease is an enzyme that chews up protein. Amyloid is a small protein,” Jones said. “Our drug enhances this. Our drug enables the chewing.”

Jones’ point is Alzheimer’s is the breakdown of the tau concrete in the microtubule bridge. 

But the “amyloid hypothesis” at the heart of Jones’ research has its skeptics.

‘Not easy on the face of it’

Derek Lowe has been noted as one of the top experts in the pharmaceutical field, having created in 2002 one of the first science blogs, “In the Pipeline.” Lowe, who himself has been on teams developing medications against Alzheimer’s and other diseases at pharmaceutical companies like Bayer and Novartis, told St. George News he is skeptical that a drug to inhibit plaque growth that can become Alzheimer’s is even possible. 

“Many people have tried over the last 30 years to develop amyloid aggregation inhibitors. That doesn’t mean that it can’t be done, but the apparent failure so far means that it’s not easy on the face of it,” Lowe said. “I’m not aware of any other drugs that work by this mechanism. When proteins aggregate, it’s a symptom of a thermodynamic sinkhole that they end up in, so keeping them from sticking together is going to be a fight.”

Lowe also said using amyloids and proteins as a target of Alzheimer’s prevention and treatments may be a lost cause. 

“I have come to have severe doubts about that,” Lowe said. “I think the eventual explanation for AD, when we finally get there, will certainly have amyloid as part of the story, but I have a lot of trouble seeing how it is truly the cause itself. And thus I have trouble seeing how targeting it can be a useful therapy, although there is of course ferocious disagreement on that point.” 

But Leavitt said that Jones has a lifetime diagnosing people with Alzheimer’s, and that experience has led to this path to Alzheimer’s prevention. 

“There’s a big, big debate about what’s actually causing Alzheimer’s. And we are firmly in the amyloid camp,” Leavitt said. “Even though people have amyloid fibrils in their brain and don’t have Alzheimer’s, everybody who has Alzheimer’s is going to have an abundance of amyloid in their brain.”

Besides whether they’re attacking the right problem, there’s another issue Jones and Leavitt say they’re well aware of: Safety.

A safe pill to swallow

Ultimately what Jones has in mind is a pill people could take along with their other vitamins that could keep them from ever developing Alzheimer’s. But even the same vitamins shaped like cartoon characters had to be made safe before they could be approved for the public. People are told to take their vitamin C, but exceeding 2,000 milligrams of vitamin C in a day could be fatal. 

Not to mention the immune response Jones and Leavitt are trying to trigger is in the brain.

“I think it’s safe to say that triggering an immune response in the brain is very dangerous business,” Leavitt said. “You don’t want to turn it on at the wrong time in the wrong place, because it can be very damaging to sensitive tissue that you can’t rebuild. And so, yeah, this is a real trick to modulate that, and we’re aware of that.”

Lowe said adding to the safety issue is the fact it will have to be taken often.

“You might need to reach significant levels of your therapeutic candidate in the brain to have a chance of this working, and for an extended time,” Lowe said. “Many years of dosing, surely. So the pharmacokinetic (how the body reacts to a drug) and overall safety barriers are significant.”

And Lowe added even if the safety issue is overcome, there’s the matter of convincing a general public to take a pill everyday for something they may never get. 

“Essentially, you’re asking to dose people who aren’t sick yet, and dose them for years,” Lowe said. “In the general population, we struggle to identify who is at greatest risk of Alzheimer’s, so it’ll be hard to narrow down to the folks that would be expected to benefit the most, if that’s your strategy.”

But Leavitt said safety is their strategy, saying that as long as he has known Jones, he has stressed toxicity. 

“These patients are probably going be older. They’re probably going to have other problems, and they’re probably going have to take this drug for decades,” Leavitt said. “So safety and toxicity has been, I mean, probably the first thing. The first thing we say is, ‘OK, is this drug going to be safe?’”

That’s where the mice come in.

‘Mice lie, monkeys exaggerate’

Inside another room at Hamit-Darwin-Freesh are what Mary Jones calls “her kids:” several mice inside plastic enclosures. Jones and her husband do have kids of their own, and she was previously a pediatrician. 

But these “kids” were required by the Federal Drug Administration as a step to prove a drug or treatment is safe before it can go to human trial. The mice, which have been genetically altered to more closely match a human genome, have been used to test the drug Hamit-Darwin-Freesh has developed. 

Advanced equipment that looks a bit like a photographer’s studio helps analyze the mice after they go through what is called a Barnes maze. Developed by University of Arizona neuroscientist Carolyn Barnes, it is used to measure memory in mice. Another piece of equipment that looks like a row of metal disks and functions like a fancy hamster wheel, called a mouse rotarod, determines the motor ability of the mice. Next to the rotorod is a piece of equipment that might be considered more gruesome: a mini guillotine used to quickly end the life of one of the lab mice to allow its brain to be sampled.  

Both control mice without the drug and those with it go through the motions of the equipment for a few days, then get about a week of rest. After that, they go through again, and the equipment is able to determine how much they have forgotten.

But Gary Jones said he isn’t a fan of the requirement that he has to test with the animals, as he doesn’t think mice will be the ultimate proof of the drug’s effectiveness or safety. 

“We have mixed feelings about the value of those studies, as do most people involved in this area, because there’s been literally no correlation drugs molecules that work in mice work in humans,” Jones said. “We’re obligated to do it. Sure. But there are people in this field now that are raised in their voices and making a case that we should not rely upon animal studies. You must test animals to be sure your drug is not toxic. But for efficacy, there are people who are raising their voices. Let’s stop this. Let’s accept the preclinical work that we do in the laboratory.”

Leavitt also isn’t convinced that the mice will be what brings the cheese.

“There’s an old science phrase: Mice lie and monkeys exaggerate,” Leavitt said. “There’s been hundreds of clinical trials that went through animal trials before that, and everything looked promising. Everybody’s really excited. And then it goes to a clinical trial, and then nothing.”

After St. George News visited the lab, those voices won out. Since the visit, Congress passed a bill that ended the FDA requirement of using animal testing before a human clinical trial, and President Joe Biden signed it into law. 

Fooled by Mother Nature

Working at the Dammeron Valley lab is by no means a 9 to 5 job for Leavitt or the Joneses. There may be someone there in the middle of the night, the middle of the morning or any other hour, and they may have been there for more than 10 hours. 

Since St. George News’ visit, the lab has added a piece of equipment called a nuclear magnetic resonance spectrometer, which despite the name is no more nuclear than a hospital’s X-ray machine. Using a superconducting magnetic field, it will allow Jones’ team to get a more thorough analysis of samples down to the molecule.

The new equipment has also magnetized Jones’ enthusiasm. 

“As I approach 77, I look forward to the day when I can participate in its clinical trial, and in doing so I will be able to evaluate patients for participation at no charge to the patient,” Jones said. “Yes, we are very confident that this one will go the full distance.”

And Leavitt said there’s never a dull moment. 

“I can’t believe it every time I come in,” Leavitt said. “I run another experiment and you know my PhD advisor would always say, ‘How’s Mother Nature going to fool us today? How is this wrong?’ And then it keeps working.”

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