‘Heroes Of CRISPR’: Vivid Yarn And Lessons Learned From A Scientific Leap Ahead

(Courtesy of NIH)

(Courtesy of NIH)

It’s being billed as biotech’s Battle Royale, an East Coast-West Coast conflict over stakes that may amount to hundreds of millions of dollars, playing out in the arcane arena of U.S. patent law.

For the story on the legal fight that kicked into full gear this week, you can read the Washington Post’s Carolyn Johnson: Control of CRISPR, Biotech’s Most Promising Breakthrough, Is In Dispute.

Everybody loves a good fight, but the import of CRISPR for humankind is not the conflict or the money. It’s that this new gene-editing technology is indisputably transforming biological research around the world, speeding up discoveries in areas from cancer to crop science.

“Medical breakthroughs often emerge from completely unpredictable origins.”

– Eric Lander

So what are the roots of this bio-revolution? And what can we learn from how it was discovered? Eric Lander explores the CRISPR backstory in a vivid scientific yarn just out in the journal Cell, available free online for the next two weeks.

Lander co-led the Human Genome Project and is now the director of the Cambridge-based genomics giant The Broad Institute, which is involved in the CRISPR patent dispute. He’s also a leading science storyteller, from popular MIT lectures on introductory biology to surely one of the most riveting episodes of The Moth ever made.

The Broad’s rivals in the patent dispute may have different versions of specific chapters (Update, 1/26: Understatement! The article unleashed a major backlash online) but Lander also draws general lessons from the CRISPR back-story:

The most important is that medical breakthroughs often emerge from completely unpredictable origins. The early heroes of CRISPR were not on a quest to edit the human genome — or even to study human disease. Their motivations were a mix of personal curiosity (to understand bizarre repeat sequences in salt-tolerant microbes), military exigency (to defend against biological warfare), and industrial application (to improve yogurt production).

The history also illustrates the growing role in biology of “hypothesis-free” discovery based on big data. The discovery of the CRISPR loci, their biological function, and the tracrRNA all emerged not from wet-bench experiments but from open-ended bioinformatic exploration of large-scale, often public, genomic datasets. “Hypothesis-driven” science of course remains essential, but the 21st century will see an increasing partnership between these two approaches. Continue reading

Further Reading

Wide Hips? Take Heart: Study Finds You Can Run Just As Efficiently

As a woman who describes herself — matter-of-factly, not self-hatingly — as shaped like a cello, I’m deeply pleased by this fascinating marathon-season report from our friends over at Boston University’s Research Website, headlined “In Defense of Wide Hips.” Re-posted with their permission:

Biological anthropologist and evolutionary anatomist Kristi Lewton of BU School of Medicine. (Jackie Ricciardi for BU)

Biological anthropologist and evolutionary anatomist Kristi Lewton of BU School of Medicine. (Jackie Ricciardi for BU)

By Kate Becker

What can you learn from a pelvis? Among the qualities that make humans unique are two physical features: our way of walking and running upright on two legs, and our newborn babies’ very large heads. Those two traits of humanity meet at the pelvis, a set of bones that includes the ilium, ischium, pubis, and sacrum.

For more than 50 years, anthropologists thought that the human pelvis was shaped by an evolutionary tug-of-war between the competing demands of bipedalism and childbirth. Now, a team of scientists that includes Kristi Lewton, an assistant professor in the department of anatomy and neurobiology at Boston University School of Medicine, and colleagues at Harvard University and Hunter College has shown that this so-called “obstetric dilemma” might not be a dilemma at all.

They found no connection at all between hip width and efficiency: wide-hipped runners moved just as well as their narrow-hipped peers.

Humans give birth to very large (“ginormous!”) newborns, says Lewton. While chimps and other nonhuman primate babies emerge from the birth canal with room to spare, human infants must perform a complicated series of rotations to make their way into the world, and the pelvic opening is just barely big enough. If something goes wrong, the lives of both mother and baby are at risk. So, why hasn’t the human body evolved a wider pelvis? Anthropologists have long believed that an evolutionary trade-off was at work; they assumed that a wide pelvis was “bad for bipedalism,” says Lewton. Yet, until now, no one had rigorously tested this assumption.

Lewton and her colleagues set out to discover whether wide hips really do make running and walking less efficient. They recruited 38 undergraduates, including both men and women, and had them walk and run on a treadmill while gauging how hard they were working by measuring their oxygen consumption. While the participants exercised, their motion was tracked by eight cameras trained on infrared markers attached to the participants’ hips, knees, ankles, thighs, and shanks. Lewton and her colleagues estimated the subjects’ hip width using the results from the infrared trackers, and later combined their data with results from a Washington University in St. Louis research team that used MRI to get a direct measure of hip width. (True hip width is defined as the distance between the hip joints, points out Lewton, and is different from what you would measure with a tailor’s tape.)

If the basic assumptions of the obstetric dilemma are right, says Lewton, participants with wider hips should run and walk less efficiently than those with narrow ones. But that wasn’t what Lewton and her team found. Continue reading

Where Does Fat Go When You Lose Weight? Mostly Into Thin Air

(Phoney Nickle/Flickr)

(Phoney Nickle/Flickr)

By Richard Knox

A couple of years ago, Ruben Meerman took off 40 pounds. And that got him wondering: What exactly happened to all that fat?

Conventional wisdom was that he “burned” it off. Or sweated it off. Or excreted it. None of that satisfied Meerman, who has a physics degree and makes his living explaining science to schoolkids and for the Australian Broadcasting Corporation.

So Meerman tackled the problem and eventually came up with a surprising answer: Most of the lost fat disappears into thin air.

More specifically, 84 percent of those fat molecules get exhaled as colorless, odorless carbon dioxide. The other 16 percent departs the body as H-2-O — plain old water.

Meerman says the discovery “got me really excited because I’d stumbled onto a gap in the knowledge. It struck me as remarkable that no one had thought this was interesting enough to pursue.”

The British Medical Journal thought so too. It has published a paper, co-authored by biochemist Andrew Brown of the University of South Wales, in its annual Christmas issue, which features off-beat (but peer-reviewed) research.

Weight Loss Realism

Meerman hopes the work will dispel misconceptions held by health professionals as well as the general public. And, he hopes it will provide a helpful dose of realism to counter the impossible expectations millions have about weight loss.

If people understand where the fat goes (and how), they’ll get “why there’s a limit to how quickly you can lose weight,” Meerman said in a Skype interview from Sydney. “And if you understand the limit, you won’t be so quickly depressed if you don’t lose 20 pounds in the first two weeks.”

First, the misconceptions. Meerman and Brown surveyed 150 professionals — split equally among family doctors, dietitians and personal trainers — about where they think the fat goes during weight loss.

By far the most common answer was that the fat was transformed into energy or heat — that is, “burned off.” About two-thirds of doctors thought so. A slightly higher proportion of dietitians did too, and about 55 percent of personal trainers.

But that would violate the Law of Conservation of Mass. It’s a basic precept of chemistry, formulated in 1789 by the French scientist Antoine Lavoisier, which holds that mass is neither created nor destroyed in chemical reactions. The total mass at the end must equal the mass at the starting point — even if matter is quite transformed in the process, from solid to liquid or gas.

The Energy Of A Bomb

Meerman points out that if fat were transformed into pure energy during weight loss, the results would be cataclysmic. Continue reading

Making Peace With My Abnormal Brain

(Andrew Ostrovsky)

(Andrew Ostrovsky)

By Dr. Annie Brewster
Guest Contributor

What you never want to hear from the radiologist: “I wouldn’t mistake it for a normal brain.”

Yet this is what I recently heard from my radiologist friend who kindly took a look at an MRI of my brain. Let me repeat: it was my abnormal brain under discussion here, and I’ll tell you, his assessment was tough to hear.

The state of my brain isn’t exactly news to me. I have had Multiple Sclerosis since 2001, and I have frequent MRIs. Moreover, as a physician at the hospital where I get my treatment, I have the dubious privilege of having complete and immediate access to my medical chart. As such, I often see the MRI images and read the reports before my neurologist does, and fortunately or unfortunately, I understand “medicalese.” (And I have radiologist friends.)

Every time I get an MRI, I devour these reports as soon as they become available on the computer, scanning optimistically for words like “stable.” I even hold onto the absurdly magical hope that old lesions will have disappeared, and that this whole diagnosis of MS has been a big mistake. Instead, I find mention of new “hyperintense foci of white matter signal abnormality” and “enhancing” lesions, “consistent with actively demyelinating MS plaques.” I fixate on words like “volume loss” and “atrophy” and in one preliminary report generated by a resident, I think I saw the word “diminutive.” Did I imagine this?

Despite the sting of these words, I am able to remain somewhat detached. As a doctor, I spend my days looking at radiology images and reading such reports.

Often — due to the formal and impersonal language that is used — it’s hard to remember that the body part being referred to is actually part of a human being. It is even harder to remember that it is part of me!

“I wouldn’t mistake it for a normal brain” penetrates deeper. I understand. My brain is under attack, and is irreparably damaged.

My first response is to mount a defense. I feel the need to tell you that my brain is still a good brain. It just has a few small blemishes. It still works! I recently passed the required ten year recertification medical boards (apparently I will never escape bubble tests), and I feel smarter than ever. I am the mother of four and the primary logistical organizer in my
household, and my (short term) memory is at least ten times better than my husband’s (no offense, honey). Furthermore, research has clearly shown that MRI findings do not necessarily correlate with clinical symptoms in Multiple Sclerosis. So there is no cause for alarm.

Also, the research is promising. Exhibit A is this massive MS conference currently underway in Boston with many great minds focusing their attention on new approaches, such as potential remyelinating therapies, to tackle the disease. (MS damages the myelin, the sheath around nerve cells, and remyelination would restore it.)

My neurologist, Eric Klawiter, at Massachusetts General Hospital, writes me this:

As a research community, we have gained a great deal of knowledge on the mechanism of remyelination and how that process can go awry in MS. There are several candidate compounds demonstrated to promote the body’s ability to differentiate precursor cells into cells that lay down new myelin (oligodendrocytes). It is yet to be established whether these candidate therapies will work best to promote immediate recovery from relapses or whether they will also be effective in the setting of remote demyelination.

Of course, any potential new therapies are years or more away and don’t do much for me right now.

So, underneath my bravado, there is vulnerability. Continue reading

Please Discuss: ‘Gene Drives,’ Sci-Fi Scary Or Cool Leap Forward?

Scientists say new "gene drive" technology could help fight malaria by affecting the mosquitoes that carry it. (Wikimedia Commons)

Scientists say new “gene drive” technology could help fight malaria by affecting the mosquitoes that carry it. (Wikimedia Commons)

Perhaps you’ve followed that teeny tiny controversy around genetically modified foods, the “GMO” debate. Or you watched the fierce back-and-forth over whether it was a good idea to modify a strain of avian flu in the lab to make it spread more easily, in order to study it.

If this is your kind of spectator sport, it’s time to learn about gene drives, a powerful new genetic technology that basically flips Charles Darwin on his head, allowing a sort of artificial selection to help chosen genes come to dominate in a population.

A paper just out in the journal eLife outlines a way to use gene drives to spread just about any altered gene through wild populations that use sex to reproduce. And a related paper just out in the journal Science calls for greater oversight and a public discourse about the potential risks and benefits of gene drive technology — now, while it’s still in early stages and confined to labs.

I can already imagine the “pro” side of the debate: “This could eradicate malaria. Reduce the use of pesticides. Bolster agriculture for a crowded planet.” And the “con” side: “But what if it goes wrong out in the wild? Have you read no science fiction?”

I spoke with two of the paper’s co-authors: Kevin Esvelt, a technology development fellow at the Wyss Institute for Biologically Inspired Engineering and Harvard Medical School, who is also the lead author of the eLife paper; and Kenneth Oye, Professor in Engineering Systems and Political Science at MIT and director of policy and practices of the National Science Foundation’s Synthetic Biology Engineering Research Center. Our conversation, edited:

CG: So what exactly is a gene drive and why are we talking about it now?

Kevin Esvelt: A gene drive is a potential new technology that may let us alter the traits of wild populations but only over many generations. We think that gene drives have the potential to fix a lot of the problems that we’re currently facing, and that natural ecosystems are facing, because it allows us to alter wild populations in a way that we could never do before.

We would really like to start a public conversation about how we can develop it and use it responsibly, because we all depend on healthy ecosystems and share a responsibility to pass them on to future generations.

So how do they work? The reason we haven’t been able to alter wild populations to date is natural selection. When you say natural selection, you think, ‘How many organisms survive and reproduce?’ And that’s pretty much how it works. The more likely you are to survive and reproduce, then the more copies of your genes there are going to be. So genes that help an organism reproduce more often are going to be favored.

The problem is, when we want to alter a species, the way we want to alter it usually doesn’t help it survive and reproduce in nature. But that’s not the only way that a gene can reproduce. We have two copies of each gene, and when organisms have children, each of the offspring has a 50% chance of getting either copy. But you can imagine that a gene could gain an advantage if it could stack the deck — if it could ensure that it, rather than the alternate version, was inherited 70%, 80%, 90%, or 99% of the time.

How gene drives affect which genes are passed down (Courtesy Kevin Esvelt)

How gene drives affect which genes are passed down (Courtesy Kevin Esvelt)

There are a lot of genes in nature that do exactly this; they’ve figured out an incredible variety of ways of doing that. Almost every species in nature has what we would call an ‘inheritance-biasing gene drive’ somewhere in its genome, or at the very least the broken remnants of one. They’re actually all over the place in nature.

The idea that we could harness these to spread our alterations through populations has actually been around for a long time. Continue reading