When I woke up this morning, having failed to crystallize on paper my scientific mulling over the weekend, I was prepared to write about the ongoing, inherent failure of science to always produce the ‘right’ answers to big questions. For decades, biologists have struggled with low rates of replication of important findings. Meta-analyses of the literature on cancer drug screening, the identity of cancer cell lines, the efficacy of ADHD drugs, the replicability of genetic association studies on disease, and even the choice of statistical tests used in major journals to prove the importance of scientific claims, have broadly demonstrated that while science eventually finds the right answers, a whole slew of initial claims (which are the most widely reported by the media due to their novelty) eventually turn out to be false.
Despite all this, scientists continue to slave away at the bench, hopeful that they might someday make a worthwhile contribution to the body of human knowledge. Moreover, the public gets its science information from such watered-down (but inspiring) ventures as I F*cking Love Science, but as a recent piece by John Skylar beautifully argued, our society appears to have a superficial love for pretty scientific pictures, as opposed to a true appreciation of the time, effort, and funding required to make this research happen. I felt uninspired, frustrated, and tormented by the conclusions these trains of thought led me to. Science is underfunded, often wrong, and even disbelieving of itself. And here I am, halfway through my PhD program, insanely determined to stay the course.
But all it took was two groundbreaking studies in fields that I am keenly interested in to fan the flames of my scientific passion and remind me why I do this. Bench science might resemble cooking, but as all scientists know, even the most methodical bench science only results in haute cuisine once in a blue moon. Nevertheless, we scientists live for these blue moons. Here are two recent, nearly coincident blue moons that reminded me why I f*cking love science.
Weekend breakthrough #1: Scientists reveal how beta-Amyloid may cause Alzheimer’s
First, we have the conundrum of Alzheimer’s research. Doctors and scientists have known for decades that beta amyloid (Aβ), a small protein found in the brain, gradually collects in ugly plaques in patients stricken with Alzheimer’s disease (AD). This Aβ hypothesis is compelling, but it is hindered by such findings that elderly people possess these plaques regardless of having the disease, and that the cognitive effects of AD appear prior to formation of plaques. No dependable treatments currently exist to either prevent AD or slow its progression, leaving the growing AD population with few options to fight their prognosis. Dozens—dare I say hundreds—of research groups have worked tirelessly for decades to try to break this problem, to no avail; I even worked for two semesters as an undergrad on a related protein, tau, that has also been postulated to cause the formation of AD plaques.
So naturally my heart skipped a beat when I caught the headline, “Scientists Reveal How Beta-Amyloid May Cause Alzheimer’s,” on the ScienceDaily website. No way. The day we’ve been waiting for, the day someone defines a mechanism for Aβ-mediated neurodegeneration; the day we can begin our work developing therapies that address the underlying cause, and not just the symptoms, of AD. That day was this past Friday. The lab of Carla Shatz at Stanford School of Medicine stumbled upon a protein found at synapses called PirB that could bind strongly to Aβ molecules floating around in neurons of mice bred to acquire AD as they age.
When these toxic Aβ molecules interacted with PirB, they initiated a biochemical cascade leading to the disassembly of synapses – the breaking of connections between neurons. Breaking these synapses would first disrupt the function of these neurons, possibly destroying the networks that maintain memories, and later leading to the death of these neurons, two consequences that happen to be clinical hallmarks of AD. Mice lacking PirB, but possessing the toxic Aβ in their neurons, were able to avoid cell death in the brain, as well as the cognitive decline seen in mice possessing both PirB and Aβ. And here’s the cherry on top: humans possess the PirB protein in their brains, albeit with a different name, LilrB2. Moreover, humans with AD appear to have enhanced signaling from LilrB2—the very signaling that degrades synapses. Shatz herself was confident about the importance this discovery, as ScienceDaily reported:
Shatz suggested that drugs that block beta-amyloid’s binding to PirB on nerve-cell surfaces—for example, soluble PirB fragments containing portions of the molecule that could act as decoy— might be able to exert a therapeutic effect. “I hope this finding will be enticing enough to pharmaceutical and biotechnology companies that someone will try pushing this idea forward,” she said.
AD researchers globally were likely first feeling dismayed that they hadn’t broken the Aβ problem themselves, while recognizing just how much new work there was to be done. I thought the weekend was over. But no, the scientific world was not about to let my weekend of scientific negativity fester further without a second glimmer of hope.
Weekend breakthrough #2: Scientists claim 100% conversion of somatic cells into iPSCs
Although stem cell therapies have tickled the imagination of doctors and scientists for years, finding a reliable source of stem cells with which to develop these therapies has been extremely challenging. The thinking goes like this: coax stem cells to build new tissues to replace damaged or diseased tissues, maybe even organs, in patients. Embryonic stem cells, which are capable of developing into any and all tissues of the body, must be harvested from human embryos. This socially-controversial idea and practice was at one point prohibited (via restricted funding) by our very own government. A team of Japanese researchers skirted this issue in 2006 by successfully converting regular adult cells (somatic cells) back into a stem-cell-like state by expressing four stem-cell genes in these somatic cells. These ‘reprogrammed’ stem cells, known as induced pluripotent stem cells (iPSCs), are nearly as effective as embryonic stem cells with regard to developing into all the tissues of the body.
Unfortunately, this discovery, which earned the lead investigator, Shinya Yamanaka, a Nobel Prize in 2012, only allowed researchers to convert under 0.1% of these somatic cells into iPSCs. Research has since expanded our understanding of iPSC generation and function, but no one has been able to significantly improve the low rates of conversion from somatic cell to stem cell. This is problematic because it takes weeks to produce only a small number of iPSCs, which must be isolated from the 99.9% of cells that have not been reprogrammed. Evidently, hundreds of researchers have been working on this problem, because I attended a conference at UCSF this past fall that focused exclusively on the reprogramming of somatic cells into iPSCs (Yamanaka was a distinguished speaker, having recently received the Nobel).
Thus, my second shock of the weekend occurred when I found a paper in Nature coming out of the lab of Yaqub Hanna at the Weizmann Institute in Tel Aviv, which claimed to have discovered a method for converting 100% of their experimental, somatic cells into iPSCs. The field has known for years now that stem cells possess chromosomes that are ‘de-repressed’ that is, capable of having all their genes expressed, compared to somatic cells whose chromosomes are largely repressed in order to encourage gene expression specific for cell type. Repression occurs when DNA is wound up into small bundles. As stem cells develop into muscle cells, for example, their DNA is progressively wound up until only muscle genes are expressed. Knowing this, Hanna’s group investigated a set of factors involved in repressing DNA during development, and tested whether knocking out any of these factors could improve the reprogramming of somatic cells into iPSCs. Their method struck gold. They discovered that knocking out Mbd3, a factor that turns on as stem cells of early embryos lose their stem-cell-ness and start to become specific tissues, improved the reprogramming of mouse and human skin cells into iPSCs to 100% efficiency. No longer will biologists need to waste their time and money purifying the 1% of somatic cells that have become iPSCs. More-efficient technologies that allow doctors to take skin cells and reprogram them into viable heart cells for cardiac patients may now be on the horizon.
Whew. I hope I didn’t lose you there and that I properly conveyed my excitement. We now have leads for developing better therapies for Alzheimer’s and better stem cell treatments for hundreds of disorders. The big problems in science often seem unsolvable, the statistics questionable, and the funding just out of reach. It’s one hell of a rollercoaster, but sometimes that blue moon rises twice in one weekend. You better be paying attention.