In the first ten years of their lives, kids born with Fanconi anemia lose the ability to make blood cells and need bone marrow transplants to survive. And although the transplant cures the bone marrow failure, people remain at greatly increased risk of cancer and rarely live past their 20s.
Unfortunately, there are no drugs to treat the underlying cause of Fanconi anemia, thought to be DNA mutations induced by molecules called aldehydes inside cells.
Part of the problem in developing a cure comes down to an inability to measure aldehydes in the blood. But that might be about to change, thanks to an interdisciplinary collaboration aided by a grant from Stanford ChEM-H.
“If we had a drug and we were doing clinical testing, we would love to be able to say, ‘here’s your aldehyde level before you started the drug, and here are the aldehyde levels in your blood cells after you started the drug,’” said Kenneth Weinberg, a professor of pediatric hematology and oncology.
If successful, such a test could help in developing a treatment to stop the aldehyde-induced DNA damage in people with Fanconi anemia and also help millions who are at risk of aldehyde-related cancers because of common genetic mutations or industrial exposure.
Not just a curiosity
Many aldehydes occur naturally. They are what gives ripening peaches their pleasant smell. One aldehyde, acetaldehyde, is what causes around 8 percent of people – and one-third of East Asians – to flush when they drink alcohol.
But over the past decade researchers have learned that in some cases aldehydes can cause strands of DNA to become tangled, preventing them from producing essential proteins and from replicating properly. In the worst cases, that tangling kills blood-forming stem cells in patients with Fanconi anemia, who lack genes needed to unravel and repair the tangled DNA.
This DNA damage is behind a number of cancers as well. The mutation in people from East Asia, for example, prevents the body from breaking down acetaldehyde and increases the risk of esophageal cancer by about a factor of 70, Weinberg said.
“I think many people have thought this mutation is just a curiosity: ‘here’s someone who, if they have a drink of alcohol, gets flushed, nauseated, headache, feels terribly ill, so they don’t drink alcohol,’” said Weinberg, who is also a member of Stanford Bio-X, the Child Health Research Institute, and the Stanford Cancer Institute. “I’m beginning to look at it as a pre-disease state rather than a curiosity.”
Testing for peach smell
Despite the growing understanding of Fanconi anemia and the role aldehydes play in promoting cancer, there are as yet no drugs to eradicate the molecules, in large part because they are as ephemeral as the smell of peaches – in other words, they evaporate too easily. As a result, conventional blood tests don’t pick them up, so researchers like Daria Mochly-Rosen, a professor of chemical and systems biology who collaborates with Weinberg, can’t tell if her efforts to create aldehyde-busting drugs are doing any good.
On the suggestion of Mochly-Rosen, who is also the George D. Smith Professor in Translational Medicine, Weinberg went to chat with chemistry professor Eric Kool a few years back. About half an hour in, Weinberg said, Kool had sketched out the idea for what would become Darkzone – a chemical that glows brightly in the presence of aldehydes.
Kool, Weinberg and their collaborators published their first results on Darkzone in 2016. Now the aim is to improve on their existing results and take the method to the clinic, where they can begin testing it on people. The challenge is twofold, said Kool, who is also the George A. and Hilda M. Daubert Professor in Chemistry. First, they want to improve Darkzone’s light output, so that it will be easier to see how much aldehyde is present in a blood sample.
Second, the team will need to develop blood-drawing equipment that maintains a consistent vacuum and prevents aldehydes from escaping the blood samples. The researchers are modifying an existing device that, rather than drawing blood from a vein, sucks blood through the skin with several hundred tiny needles. That blood could then be fed into a vacuum-sealed device preloaded with Darkzone.
Beyond disease and mutations
The principle aim, as Weinberg said, is to help develop better drugs for Fanconi anemia and aldehyde-related cancers.
But there is another, perhaps equally important application down the road. Aldehydes – including formaldehyde and acetaldehyde – are everywhere. “Right now, you’re sitting at a laminated wooden desk and you are breathing in small amounts of acetaldehyde,” Weinberg said, which are prevalent in plywood, paint and electronics.
And if it’s bad for those of us sitting at laminated wooden desks, it’s worse for those who make those products, especially in countries – many in East Asia, no less – where aldehydes are less tightly regulated. “Aldehydes are industrial toxins, so it would be fantastic if we had the ability to measure people’s exposure and use that to drive efforts to mitigate their exposure to these chemicals,” said Weinberg, who is also the Anne T. and Robert M. Bass Professor in Pediatric Cancer and Blood Diseases.