What's "The Best" Way to Get from Point A to Point B?

Would you rather take a five-minute walk on crowded sidewalk next to four lanes of honking traffic on a clogged urban artery, or a seven-minute stroll down the leafy neighborhood street two blocks over?

Much of the time, we determine “the best” way to get somewhere as a function of either time or distance – seeking out the fastest drive, the nearest bus stop, or the shortest walk, for example. We ask ourselves if it is quicker to drive or walk, or whether it’s easier to ride or take the subway.

If speed is your thing, then check out the latest installment in the You Are Here series at the MIT Media Lab’s Social Computing Project. The new package, called “Best Mode of Transportation,” still defines “best” as “fastest,” but it offers a data-driven comparison of modes, against which we can check our mental calculations.

The results might surprise you. As Emily Badger writes on the Washington Post’s Wonkblog, “Cycling is a much more efficient mode of transportation than many people realize. And transit is startlingly not so. Seldom will it get you farther, faster, than a bike will.”

Behind bicycling, driving is nearly always the second-fastest way to get most places within cities. Transit is, for the most part, a distant third. This does vary by location – the Manhattan model shows the substantial impact of a dense transit network (as well as the effect of an urban corridor that is extremely long and very narrow).

But for most of us, at least sometimes, speed isn’t always the top consideration.

If beauty is your thing, Yahoo Labs in Spain tells us how we can be less concerned with arrival, and more focused on enjoying the trip.

Instead of determining the fastest route, these researchers have found a way to measure the most beautiful (or quietest, or even happiest) paths between destinations. It involves a lot of crowdsourcing, including data-mining Flickr (which is owed by Yahoo) for geotagged photos and then measuring the moods of words those photos have been tagged with. You can read the full paper here, and a less technical description here, but the high-level message is that it is often possible to find a route from where you are to where you want to be that will be significantly more enjoyable to travel, and only slightly longer than the fastest way.

There are other factors in play in choosing how to get from point A to point B, of course. Not only might different people make different choices based on their own tendencies, but given other aspects of the decision (such as cost, safety, personal comfort, reliability, where you have to go next), you might yourself choose different priorities on different days or at different times of day.

We should aspire to give people choices that enable as many of them as possible to have their desired outcome, whether that is a fast arrival, a quiet stroll, a scenic bike ride, or something else altogether. If these two data-driven approaches can be combined, it might just give us the ability to design transportation options that strike the right balance among all the various attributes that travelers are looking for when taking a trip.

New Science on Sea-Level Rise Is a Call to Immediate Action

The announcement Monday that several key glaciers that form part of the West Antarctic Ice Sheet are in an irreversible cycle of melting, and will raise global sea levels significantly by the end of the century and disastrously over the course of several centuries, was widely reported. As it should have been, given the effects global warming are having, and will continue to have, on life here on Earth.

But none of the coverage I saw included the fact that parts of the Greenland Ice Sheet had entered the same sort of cycle as much as a decade ago. In fact, just one glacier – the Jakobshavn Isbrae – on its own contributed 3 percent of worldwide sea-level rise over the past 10 years.

Back in March, when I was working as a freelance journalist, I interviewed the two scientists whose research is central to yesterday’s announcement, and found them both concerned about what their data were showing.

There is uncertainty about just how quickly these cycles can move. Exposure to ocean currents and warming waters dramatically accelerates calving and melting of glaciers, in part because the water pushes the ice around, whether it is floating or grounded on the sea floor.

As a result of these effects, Jakobshavn, for example, has tripled its speed toward the ocean in 20 years. You might have seen this glacier calve in the 2012 film Chasing Ice: It was the glacier that calved a mile of ice in a single event, a scene spectacular in its power and scary in its import for those of us who live near the ocean.

Eventually, perhaps in about 100 years, Jakobshavn will retreat so far that it will be landlocked and no longer a significant contributor to sea-level rise. But the topography beneath the West Antarctic Ice Sheet glaciers is very different, getting farther and farther below sea level as one moves toward the center of Antarctica, meaning that as the glaciers retreat their exposure to the melting and calving effects of the ocean will only grow. They will only melt faster and faster, until they are entirely gone.

These are only some of the effects of global warming that are already in the pipeline, resulting from emissions we have already released into the atmosphere. Monday’s announcement is a crucial reminder that we must both adapt to the changes that are already inevitable, and step up our efforts to forestall the even more calamitous and rapid changes scientists warn are in store if we fail to reduce our emissions of greenhouse gases.

The world has the tools now to begin reducing carbon emissions, conserving energy, and transitioning to renewable sources of power. We must act to prevent other irreversible cycles from beginning to transform Earth beyond our ability to adapt – or even contemplate.

Making clinical trials more diverse

Published in Drug Discovery News

WASHINGTON, D.C.—Hoping to expand both statistical validity of clinical trials and access to experimental therapies beyond their current confines, major medical-industry players have united to launch a campaign called “I’m In,” encouraging minorities and their doctors to find out about, and participate in, clinical medical-research trials.

 

While encouraging African Americans, Asian Americans, Hispanics and members of other ethnic groups to join medical research, speakers at a March 12 press event announcing the initiative were cognizant of the shadow of the Tuskegee syphilis experiments, an unethical and long-condemned study of the spread of untreated syphilis in African-American men that ran from the 1930s to the 1970s.

 

While Dr. Carlos Cardenas, board chairman of Doctors Hospital at Renaissance in Edinburg, Texas, alluded more vaguely to the idea of “removing any and all stigma that is associated with being part of a clinical trial,” another speaker, Averl Anderson, a breast-cancer survivor and participant in clinical trials, mentioned Tuskegee by name as a reason “people have a lot of mistrust in medical research”—particularly in the African-American community, she said.

 

But they and others representing a range of partners in the new campaign stressed the importance of broadening participation.

 

“These breakthroughs do not happen on their own,” said John Castellani, president and CEO of Pharmaceutical Research and Manufacturers of America, but rather rely “very heavily on volunteer participation in clinical trials.”

 

Years of work by the pharmaceutical industry to increase diversity in trials have not borne the hoped-for fruit: “African Americans, Asian Americans, and Hispanics are still dramatically underrepresented in clinical trials,” he said.

 

As Castellani said, “the future of medicines is going to be aimed more and more at genetically homogeneous populations,” which means drawing more from minority populations to properly test drugs—especially those aimed at diseases those populations suffer from disproportionately.

 

For example, prostate cancer is twice as fatal for African Americans as Caucasians, according to material distributed in advance of the campaign kickoff—and yet only 4 percent of prostate-cancer clinical trial participants are African American. Cancer is the top cause of death for Asian Americans, but just 2.8 percent of cancer trials patients are Asian American. And despite the higher prevalence of diabetes in the Hispanic population, only 1 percent of all trial members are Hispanic.

 

Based on early glimpses, the campaign is centering on personal connections to family members and the wider community of each minority group. A video promoting the effort included lines like “It’s not enough to wait for someone else to act” and “We all have a responsibility to each other and future generations.”

 

Gary Puckrein, president and CEO of the National Minority Quality Forum, noted that by 2020, more than half of Americans will be members of groups now called “minorities,” leading him to argue that “underrepresentation of minorities affects everyone.”

 

He said this is a campaign to help test “medicines for a biodiverse America.”

 

Cardenas offered an example: When he started practicing medicine, there was just one medication for hypertension; he noticed, though, that it didn’t work the same in people with Hispanic backgrounds as it did in those with non-Hispanic heritage.

 

“How are we to know how our patients will respond to these medications?” he asked. “It’s something we should not leave to chance.”

 

Anderson, for her part, said she is a five-year breast-cancer survivor. She was diagnosed in 2009 with stage three, triple-negative cancer, “a very aggressive form of breast cancer that’s common in African-American women.” Her doctor suggested she participate in a trial, which she credits with her survival.

 

That’s another key element beyond encouraging individuals to participate, said Dr. Ho Luong Tran, founding president and CEO of the National Council of Asian Pacific Islander Physicians.

 

“As physicians we must recognize our role as trusted healthcare providers,” she said. Doctors “owe it” to their patients to “share all possibilities” for treatment, including clinical trials. She said more than two-thirds of Americans report being likely to join a clinical trial if their doctor suggests it, but only 22 percent of people say they have had such a conversation.

 

Citing statistics that 38 percent of Hispanics, 36 percent of Asian Americans, 33 percent of African Americans and 42 percent of non-Hispanic whites say doctors have the greatest impact and the greatest responsibility to talk about trials and research, Tran called on her fellow doctors to learn about, support and encourage their patients to join trials. “If we don’t talk to them about clinical research, few others will,” she said.

 

Puckrein said the website for I’m In, at www.JoinImIn.org has options to register as a member of the public, an interested doctor, and even as a trial researcher, to allow all three groups to connect with each other more efficiently.

Merck HIV therapies make big news at CROI

Published in Drug Discovery News

NEW YORK—Two separate HIV therapies manufactured by Merck, one new and the other a groundbreaking favorite from the past, had big announcements at the 21st Conference on Retroviruses and Opportunistic Infections in early March.

 

It was just a peek at the newcomer, doravirine (MK-1439), looking at data from the first 24 weeks of the first part of a two-segment 96-week trial comparing doravirine to the current standard of care, efavirenz (Bristol-Myers Squibb’s Sustiva).

 

“This study is really the first data we have,” apart from a very small, very short monotherapy study, said Dr. Hedy Teppler, executive director, infectious diseases at Merck Clinical Research, who was also an investigator on the trial.

 

This was a Phase 2 trial (Phase 3 will come later in 2014), in which a range of once-daily doses, 25 milligrams, 50 mg, 100 mg and 200 mg, were used in combination with once-daily doses of emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences’ Truvada.

 

“It certainly performed at least as well as efavirenz,” she tells DDNews. Merck is hoping doravirine will be better in terms of both tolerability and potency that existing drugs, and with less central nervous system toxicity.

 

“Each dose compared well,” according to Teppler—in fact, the data didn’t distinguish one dosage as being more effective than the others. Additional information, though, led to the choice of 100 milligrams to be the dose for the remainder of the 96-week trial and other further studies.

 

Teppler says those factors included providing a reasonable dosage level to discover potential negative drug interactions, and to explore the drug’s overall usefulness.

 

“Choosing the 100-milligram dose should protect against needing to do any dosage adjustment,” Teppler says.

 

For those not candidates for efavirenz (such as women of child-bearing age or people with central nervous system issues), another study offers hope. Merck’s drug Isentress (raltegravir), the first integrase inhibitor approved by the FDA (in 2007), featured in a new study by the AIDS Clinical Trials Group. It compared Isentress given twice daily against atazanavir (Bristol-Myers Squibb’s Reyataz) and darunavir (Tibotec’s Prezista), both given once daily. (All patients also got Truvada daily.)

 

While Merck itself had looked at Isentress versus efavirenz, and found positive results, the ACTG “felt there was a need to look at options in patients who were not candidates for efavarinz,” said Randi Leavitt, senior director, clinical research, global clinical development—infectious disease at Merck, such as women of childbearing age or people with central nervous system issues.

 

The 96-week ACTG study (ACTG 5257) looked at 1,800 treatment-naive patients, a quarter of whom were women, 34 percent non-Hispanic white, 42 percent non-Hispanic black and 22 percent Hispanic.

 

The study found encouraging news for Merck, Leavitt tells DDNews. First, “all three regimens were basically equivalent with regard to efficacy.” But when combining that result with tolerability, “raltegravir was superior to the other two regimens.”

 

And while Isentress has been criticized for being a twice-daily medicine up against once-daily competitors, the results showed that “if the drugs are well tolerated, people will be compliant with a twice-a-day regimen,” Leavitt said.

 

Nevertheless, the company is working on a reformulation to make a once-daily 1,200-mg dose available. That follows on the 2011 report of the failure of tests of an 800-mg daily dose; Leavitt said those results “provided a lot of information” that have improved expectations for the new formulation.

Smash and grab

Published in Drug Discovery News

LA JOLLA, Calif.—Scripps Research Institute scientists have devised two highly specific methods to create new drugs, one that flings a single atom as a wrecking ball and another that can find therapy targets in tiny folds of microRNA.

 

A paper published in Nature in March describes research by Scripps chemistry professor Jin-Quan Yu that builds on his earlier groundbreaking development of using a weak chemical bond in molecule frameworks previously thought to be an obstacle, instead turning it into a powerful advantage when building drug compounds.

 

To attach function groups to chemical frameworks, a C-H bond must be broken—and it must be a specific, and possibly different, one for each potential intended attachment option.

 

“The best way to make a molecule is to replace a C-H bond directly,” Yu tells DDNews.

 

Some C-H bonds, though, don’t react, and are far away from attachment points of potential catalysts, rendering them difficult to break. With previous methods, “you cannot make certain types of molecules,” Yu says.

 

Yu’s insight, which he has been developing since 2002 at the University of Cambridge, was that he could install nitrile groups—weak connections that were dismissed in the past as hurting the structure of a framework—and use that weakness to facilitate the swinging of a catalyst across the molecular distance to a remote C-H bond, allowing it to be broken.

 

At that point, just as with other broken C-H bonds, functional groups that are building blocks for drugs can be attached, Yu said.

 

He originally published about the technique for what is called “meta” C-H activation inNature in 2012; the most recent paper has both simplified the process and allowed it to be applied more specifically to targeted C-H bonds.

 

“The key is to tune the shape of the template to create a subtle bias towards the targeted carbon hydrogen bond,” Yu said in Scripps’s announcement of the paper. “At the same time the template’s movement towards the target site has to be exploited effectively by a super-reactive catalyst.”

 

The chemical reagent involved will be available through Bristol-Myers Squibb’s catalog for order by laboratories, so that other researchers may use it in their own work, including targeting compounds common in drug discovery, such as tetrahydroquinoline, benzooxazines, anilines, benzylamines, 2-phenylpyrrolidines and 2-phenylpiperidines. “All these are commonly used in medicinal chemistry either as final drug compounds or intermediate compounds from which the final compounds are made,” Yu notes.

 

And in the future, he expects to further refine the technique so that the nitrile groups can be used catalytically, rather than needing to be installed and later removed.

 

The other approach, developed by Matthew Disney at the Scripps Florida campus, also inverts a standard method of searching for binding opportunities, this time in microRNA folds. Where previously researchers had to take RNA structures and do high-throughput screenings to find binding opportunities, Disney has built a database of potential types of bonds between RNAs and small-molecule function groups.

 

Then, by comparing given RNA sequences—not structures—to the database, Disney’s method can pinpoint possible opportunities. Only then does attention turn to the structures themselves, he tells DDNews: “Once we identify these interacting partners, could we find them … and drug it?”

 

Every disease has a relation to RNA, he said, because proteins play key roles in the process.

 

“If there’s some toxic protein … we can potentially target the RNA that makes that protein,” Disney says. (Alternately, if a disease causes too little of a protein to be produced, his technique can boost production.)

 

As a test case, and proof of concept, Disney and his team identified a druggable target—and its corresponding drug—in MiR-96 microRNA, which is believed to delay cell death by obstructing apoptosis, a natural cell-death process that begins when cells begin to grow in ways that are otherwise uncontrollable.

 

“People think that RNA can’t be drugged with a small molecule,” Disney says, but his approach proves that belief wrong. And it offers the prospect of very tightly targeting cells, in a way much narrower than the broad targeting approach taken today, where non-disease-related cells are also affected by therapies.

 

Next, Disney will go after diseases without current cures, such as Ebola, as well as orphan diseases that may need therapeutic-research attention.

 

While resistance to microRNA-targeting drugs is possible, Disney said his approach would help respond: “If resistance were to happen, and the RNA structure were to change,” then they could go back to the database and find binding matches for the new structure, he says.