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Saturday, January 5, 2019

Coverage denied Medicaid patients as layers of private companies profit


Marcela Villa isn’t a big name in health care — but she played a crucial role in the lives of thousands of Medicaid patients in California. Her official title: denial nurse.
Each week, dozens of requests for treatment landed on her desk after preliminary rejections. Her job, with the assistance of a part-time medical director, was to conclusively determine whether the care — from doctor visits to cancer treatment — should be covered under the nation’s health insurance program for low-income Americans.
She was drowning in requests, she said, and felt pressed to uphold most of the denials she saw. “If it was a high-dollar case, they tried to deny it,” Villa said. “I told them you can’t deny it just because it’s going to cost $20,000.”
Villa, 32, did not work for the government. She did not even work for an insurer under contract with the government. She worked for a company now called Agilon Health. Owned by a private equity firm, it’s among the legion of private subcontractors looking to profit from Medicaid patients.
California’s Medicaid program, known as Medi-Cal, has determined that the Long Beach company, which was paid to coordinate care for about 400,000 patients, improperly denied or delayed care for at least 1,400 of them, state officials confirmed. The state Department of Managed Health Care is investigating further.
The state findings, along with internal company documents and a whistleblower complaint obtained by Kaiser Health News, shine a light on the potential dangers of outsourcing care for poor people. Government oversight, not rigorous to begin with, fades as taxpayer money filters down through layers of companies eager to seize on Medicaid’s substantial growth under the Affordable Care Act. Medicaid officials say they have authority only over the health plans, not their subcontractors.
In an interview, Agilon chief executive Ron Kuerbitz acknowledged that some patients experienced modest delays in care but disputed that any suffered unjustified denials. He noted that an internal investigation by the company found no evidence of “systemic” denials and that most of the problems existed before Agilon took over another firm, Primary Provider Management Co., in 2016.
“We did the right thing when it was identified,” Kuerbitz said of the problems. “We disclosed it, we investigated it, and we pursued a remedial path.”
Such concerns are not isolated to one company. Last year, KHN reported on similar irregularities at SynerMed, a Medicaid subcontractor that coordinated care for about 650,000 patients in California.
In response to a whistleblower complaint, the state Medicaid program said it found “widespread deficiencies” at SynerMed that put patients “in imminent danger of not receiving medically necessary healthcare services.” The company’s staffers had falsified documents for years to cover up improper denials of care, according to state officials.
Then SynerMed abruptly shut down, and some of its patients moved to Agilon’s medical groups.

SKIMPING ON SERVICES?

Nearly three-quarters of the 73 million low-income Americans on Medicaid are now in managed care, in which states pay health insurers fixed monthly amounts for each enrollee to cover the range of services they need.
Under this system, keeping patients as healthy as possible is one way to make money. Another is to deny or skimp on services.
Increasingly, Medicaid plans outsource the work of managing patients’ health and medical treatment to subcontractors like Agilon — passing along a share of the government money coupled with the financial risk posed by a fixed budget.
These firms can be powerful gatekeepers. They run physician groups, bear responsibility for forming doctor networks and judge whether a request for care is necessary.
Agilon is a big player in California — doing business with insurers such as Molina Healthcare and Blue Shield of California — and it’s now expanding in other states like Texas and Ohio.
Primary Provider Management Co. ran several medical groups, including Vantage Medical Group with more than 5,000 physicians across Southern California. By building off PPMC’s base of Medicaid enrollees in California, the New York private equity firm that owns a majority stake in Agilon — Clayton, Dubilier & Rice — sought to coordinate care in Medicaid and Medicare Advantage plans across the country. (CD&R did not respond to interview requests.)
For several years, the problems at PPMC, and then Agilon, went undetected. Then, in early 2018, Agilon disclosed to the California Department of Managed Health Care its discovery that employees had been altering records prepared for auditors, which it said was not known to top management.
According to an internal report, completed in May and obtained by KHN, staffers had been falsifying documents since at least 2014 to pass audits by health plans. Employees were changing dates, for example, to cover up delays or withholding certain files so they couldn’t be reviewed.
That same month, an anonymous whistleblower sent a letter to health plans and government officials, urging them to investigate “illegal, unethical” conduct at the firm. “Senior management delays treatments for cancer patients without any regard of patient’s well-being, to save their dollars,” the whistleblower wrote in a two-page letter reviewed by KHN. “They brag about how profitable we are.”
In response to the allegations raised by the whistleblower and state, Agilon opened another internal investigation. That second report, finished in June, found inadequate staffing to handle the volume of work, various shortcuts and practices outside industry “norms” and improperly denied claims. Both internal reports were released to the state.
A top official Inland Empire Health Plan, one of the largest Medicaid insurers in the country, said the plan also looked into Agilon’s conduct and found instances in which its patients were harmed.
In an interview, Inland Empire CEO Bradley Gilbert said Agilon denied a patient’s transfusions for anemia, causing the person to be hospitalized. It also improperly denied cardiac rehabilitation to a patient recovering from a heart attack, he said. Inland Empire canceled its contract with Agilon’s Vantage Medical Group in August, he said.

A ‘MANAGER TOLD ME TO DO IT’

Agilon’s June report depicts an operation that was often stretched thin: Nurses were handling 120 to 200 requests for care per day, on average, with no full-time medical director to review the findings.
From 2014 until May, the company relied on a family physician who was working 10 to 12 hours a day running his own medical practice, according to the report.
Dr. Reuel Gaskins was busy seeing his own patients at the Hampton Medical Clinic in Riverside, Calif., where a red neon sign flashes “Open” in the front window. In an interview, Gaskins said he reviewed cases during breaks throughout the day and after normal work hours. He said he left Agilon in April.
Ultimately, Agilon’s internal investigation found that patient care may have been denied 439 times since 2014 without a physician’s review of the medical records — a potential violation of state law. Under California law, only a licensed physician or health care professional who is “competent to evaluate the specific clinical issues involved” can determine medical necessity.
Gaskins said he was not aware of allegations that medical decisions were made without his review until he was interviewed by Agilon’s lawyers.
“That’s inappropriate and unacceptable,” he said. “It really bothered me when I heard about it.”
The June report also found that Villa helped alter 20 files at the request of a supervisor in 2014 so her employer could pass an upcoming audit by an insurer.
A “manager told me to do it,” Villa said in an interview. “They were so adamant that everything look perfect for the auditors.”
A few days after the company’s lawyers made that discovery, Agilon sent Villa home on paid leave, the nurse said. She said that when she returned to work in August, she found she had been replaced as denial nurse, and shortly after that, she was fired.
Meanwhile, in recent months, Agilon has mended its relationships with some insurers and won new Medicaid contracts.
Consumer advocates worry that the concerns surrounding Agilon and SynerMed signal a much larger problem in the burgeoning Medicaid managed-care industry.
“These private entities get very little oversight,” said Linda Nguy, a policy advocate at the Western Center on Law & Poverty in Sacramento, “and there’s real harm being done to patients.”
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Hospitals post prices online; patients remain befuddled


As of Jan. 1, in the name of transparency, the Trump administration required that all hospitals post their list prices online. But what is popping up on medical center websites is a dog’s breakfast of medical codes, abbreviations and dollar signs — in little discernible order — that may initially serve to confuse more than illuminate.
Anyone who has ever tried to find out in advance how much a hospital test, procedure or stay will cost knows the frustration: “Nope, can’t tell you” or “It depends” are common replies from insurers and medical centers.
While more information is always welcome, the new data will fall short of providing most consumers with usable insight.
That’s because the price lists displayed this week, called chargemasters, are massive compendiums of the prices set by each hospital for every service or drug a patient might encounter. To figure out what, for example, a trip to the emergency room might cost, a patient would have to locate and piece together the price for each component of their visit — the particular blood tests, the particular medicines dispensed, the facility fee and the physician’s charge, and more.
“I don’t think it’s very helpful,” said Gerard Anderson, director of the Johns Hopkins Center for Hospital Finance and Management. “There are about 30,000 different items on a chargemaster file. As a patient, you don’t know which ones you will use.”
And there’s this: Other than the uninsured and people who are out-of-network, few actually pay full charges.
The requirement to post charges online in a machine-readable format, such as a Microsoft Excel file, came in a 2018 guidance from the Trump administration that builds on rules in the Affordable Care Act. Hospitals have some leeway in deciding how to present the information — and currently there is no penalty for failing to post.
“This is a small step” toward price transparency amid other ongoing efforts, Centers for Medicare & Medicaid Services Administrator Seema Verma said in a speech in July.
But finding the chargemaster information on a hospital’s website takes diligence. Patients can try typing the hospital’s name into a search engine, along with the keywords “billing” or “chargemaster.” That might produce a link.
Even when consumers do locate the lists, they might be stymied by seemingly incomprehensible abbreviations.
The University of California San Francisco Medical Center’s chargemaster, for example, includes a $378 charge for “Arthrocentesis Aspir&/Inj Small Jt/Bursa w/o Us,” which is basically draining fluid from the knee.
At Sentara in Hampton Roads, Va., there’s a $307 charge for something described as a LAY CLOS HND/FT=<2.5CM. What? Turns out that is the charge for a small suture in surgery.
Which services, treatments, drugs or procedures a patient will face in a hospital stay is often unknowable. And the charge listed is just one component of a total bill. Put simply, an MRI scan of the abdomen has related costs, such as the charge for the radiologist who reads the exam.
Even something as seemingly straightforward as an uncomplicated childbirth can’t easily be calculated by looking at the list.
Comparisons between hospitals for the same care can also be difficult.
An uncomplicated vaginal delivery charge at the Cleveland Clinic’s main campus is $3,466.
Looking for that same information on the Minnesota Mayo Clinic‘s online chargemaster page shows two listings, one for $3,030, described as “labor and delivery level 1 short” and the other for $5,236, described as “labor and delivery level 2 long.” But, what’s a short labor? What’s a long one? How is a patient who didn’t go to med school supposed to know the difference?
Also, those are just the charges for the actual delivery. There are also per-day room charges for mom and the newborn, not to mention additional charges for medications, physicians and other treatments.
To get at the total estimated charge, California requires hospitals to report charges for a select number of such “bundles” of care, called “diagnosis-related groups,” or DRGs, in Medicare jargon.
At the University of California-San Francisco’s hospital, for example, there are two chargemaster line items for vaginal childbirth: One is $5,497 and the other is $12,632. But there’s no indication how these differ. Consumers might then turn to the “bundled” cost based on those DRGs, where the ancillary costs are included. That lists the total charge for an uncomplicated childbirth at an astounding $53,184.
A UCSF spokeswoman said no officials were available to comment on this figure.
Though chargemaster rates are quite different from the lower, negotiated rates that insurers pay, they do become the basis for what patients pay who are without insurance or who are treated at hospitals outside their insurer’s network. Out-of-network patients are often surprised when they get what are called “balance bills” for the difference between what their insurer pays toward their care and those full charges.
Still, even knowing chargemaster rates “would be entirely unhelpful” in fighting a high balance bill, said Barak Richman, a law professor at Duke University who has written extensively about balance bills and hospital charges.
“Chargemasters are enormous spreadsheets with incredibly complicated codes that no one short of a billing expert would be able to make sense of,” he said.
Nevertheless, some experts say that merely making the charges public shines a light on the often very high — and widely varying — prices set by facilities.
Even if those charges are only “what hospitals would like to receive,” posting them publicly could make hospitals “totally embarrassed by the prices,” said Anderson at Hopkins.
Billing expert George Nation, a finance professor at Lehigh University, said that rather than posting chargemaster lists, hospitals should be required to provide the average prices they accept from insurers. Hospitals generally would oppose that, saying negotiated rates are a trade secret.
It’s unclear that the lists will have much impact. “It’s been the norm here in California for over a decade,” said Jan Emerson-Shea, vice president of external affairs for the California Hospital Association. Even so, “from a practical standpoint, I’m not sure how useful this information is,” she said. “What an individual pays to [the] hospital is going to be based on what their insurer covers.”
That could include such things as the annual deductible, whether the facility or physicians involved in the care are in-network and other details.
“The hospital piece is just a small piece,” said Ariel Levin, senior associate director for state issues at the American Hospital Association.
Still, “the biggest concern is it falls short of that end goal because it really doesn’t help consumers understand what they are going to be liable for,” she said.
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2 years after sluggish 2016, new drug approvals hit their stride in 2018


If in 2017, the FDA was trying to make up for lost time, the agency went into overdrive in 2018, approving more than 50 new molecular entities. The strong showing in 2018 followed a more-than-respectable 46 NMEs the previous year, which came after an anemic 2016 that saw only 22 approvals.
By the FDA’s count, it approved 59 NMEs in 2018, topping its previous record of 53 in 1996. If you’re wondering why our count is different, there are multiple reasons. We included two biologics—Andexxa and Jivi—and Inbrija, a new formulation of levodopa, in our list. We omitted other drugs, such as Akynzeo. The combination of netupitant and palonosetron first earned the FDA’s OK as an oral drug for the prevention of nausea in patients undergoing chemotherapy in 2014. The FDA approved an injectable version of Akynzeo that uses a prodrug of netupitant for the same indication in 2018 and listed it as an NME. We also omitted Omegaven, the active ingredient of which is fish oil triglycerides, and Annovera, a contraceptive ring that releases hormone medications that are already available on the market. And though the FDA listed cancer drugs Braftovi and Mektovi separately, we considered them a combination treatment, like Zepatier (elbasvir/grazoprevir) in 2016.
With that out of the way, let’s get down to what happened in 2018.
Predictably, cancer drugs came out tops with 16 approvals,with blood cancer treatments coming out slightly ahead of those for solid tumors. AstraZeneca’s Lumoxiti and Verastem’s Copiktra were both approved as third-line treatments for blood cancers—the former for hairy cell leukemia, a rare, slow-growing cancer, and the latter for chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma.
Several drugs were indicated for genetically defined cancers: Array BioPharma’s Mektovi/Braftovi for BRAF-mutated melanoma and Agios’ Tibsovo for relapsed or refractory acute myeloid leukemia with an IDH1 mutation, as well as a trio of drugs from Pfizer, namely Vizimpro for EGFR-mutated non-small cell lung cancer, Lorbrena for ALK-positive NSCLC, and Talzenna for BRCA-mutated, HER2-negative breast cancer. And who could forget Bayer and Loxo’s Vitrakvi, the “tissue-agnostic” drug that won approval to treat patients whose tumors feature a neurotrophic receptor tyrosine kinase gene fusion?
The number of rare disease approvals almost matched that of cancer approvals. Thrombocytopenia saw two new approvals in Doptelet and Tavalisse, as did hereditary transthyretin amyloidosis (hATTR) in Alnylam’s Onpattro and Akcea/Ionis’ Tegsedi. Onpattro also had the distinction of being the first approved drug for polyneuropathy stemming from hATTR, as well as the first small interfering RNA, or siRNA, medicine.
GW Pharma’s Epidiolex became the first cannabis-based medicine to get past the FDA. Approved for two rare forms of epilepsy, Dravet and Lennox-Gastaut syndromes, Epidiolex’s active ingredient is cannabidiol, a Schedule I drug with “no currently accepted medical use,” which had to be rescheduled by the Drug Enforcement Administration (DEA) before GW could roll it out. While the DEA only rescheduled cannabidiol in the form of Epidiolex, GW Pharma’s historic approval could pave the way for other companies working on cannabis-based treatments.
Hepatitis C, the indication that seemed to keep on giving, at least these past few years, was absent from 2018’s crop, while HIV and migraine logged three new drugs apiece. Gilead’s HIV combo drug, Biktarvy, is expected to garner as much as $10 billion in sales, arriving in time to help stave off pressure on the Big Pharma’s hepatitis C franchise. And TaiMed’s Trogarzo, approved for multidrug-resistant HIV-1, is the first HIV therapy with a new mechanism of action approved in more than a decade.
Migraine was also a hot area, with several players racing to get a first-in-class nod for their CGRP inhibitors. Amgen and Novartis won that distinction with Aimovig, which was approved in May. Teva’s Ajovy and Eli Lilly’s Emgality followed suit in September, but there are still more to come. Allergan and Biohaven are both working on oral CGRP drugs, which represent a more attractive option for patients.
As individual drugmakers go, there was one clear winner: Pfizer, which didn’t get a drug approved until September but ended up with four approvals—all in oncology—over the course of two months. Its second approval of 2018, PARP inhibitor Talzenna, earned the FDA’s OK for BRCA-mutated, HER2-negative breast cancer, but the Big Pharma is looking to expand its repertoire to other cancers, including ovarian, pancreatic and lung.
Most of the other companies on this year’s list got just one approval apiece, with the exception of Shire and AstraZeneca, which both got two. Bayer, Eli Lilly, Novartis, and Shionogi also got two, but their second approvals were all for partnered drugs. For the second year in a row, Bristol-Myers Squibb was the only top 15 pharma company that went without.
So what was behind the boost in drug approvals in 2018? Evercore ISI analyst Jon Miller says it’s hard to say that there’s a trend across the board: “The most I would say is these things go in waves. That said, the agency over the past couple of years has been increasingly conciliatory. And I don’t mean that they necessarily are letting bad drugs through, but they have been maybe putting up less resistance to certain things.”
He pointed to the controversial approval of Exondys 51 in 2016 as the bellwether for this: “The FDA is becoming more willing, especially in rare diseases and restricted patient populations with high unmet need, to approve drugs on what might have counted as thin evidence five or 10 years ago.”
And while some people thought Exondys had been approved on “relatively shaky evidence,” Miller said that it didn’t necessarily mean that the FDA was going to approve everything that came its way. He doesn’t think the evolution in the agency’s thinking is limited to the past two years: “I think this is a trend that has been developing for a little while and there are natural ebbs and flows in the approval cycle, as pipelines ebb and flow naturally.”
A more telling statistic would be approval rate, he said, or the number of new drug applications that are approved each year as a percentage of total applications filed. But this can be hard to track, as the FDA does not publicly release applications that are submitted but not approved, and the only real source for rejected applications is when a company announces that it has received a complete response letter, a request for more data, or the like. The FDA did not respond to a request for comment by press time.
“According to the regulator’s own statistics applications have also risen, but not at the same rate; although not much data have been seen for 2018 yet. This uptick presumably largely reflects the FDA’s internal efforts to get new drugs to market more quickly and efficiently. Many believe that the jump in numbers is also a result of lower efficacy hurdles,” wrote EP Vantage in its 2019 Preview.
One question is what this “clement regulatory climate,” to quote Vantage, might mean for the future.
“A lot of this bull market has been driven by a super-permissive FDA. This has emboldened risk-taking by both biotech companies and investors,” one investor, who asked not to be named, told Vantage.
“[If] this surge in accelerated applications is a symptom of an industry that has been encouraged to push forward too quickly—in some cases to the detriment of both patients in terms of effectiveness and safety and investors in terms of weak commercial prospects—an era of regulatory permissiveness could hurt the sector over the longer term,” Vantage wrote.
Without further ado, here’s our list of drugs that earned FDA approval in 2017.
Special Report—2 years after sluggish 2016, new drug approvals hit their stride in 2018
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NYC Health & Hospitals designs plant-based diet to aid chronic disease patients


In the past few years, a growing number of studies have shown that plant-based diets can help prevent and even reverse chronic conditions like heart disease, Type 2 diabetes and obesity.
As an example: a 2015 meta-analysis in the Journal of the American Heart Association found people who adopted a vegetarian diet lowered their cholesterol levels, which can reduce the risk of heart disease.
Backed by this evidence, as well as advocacy from Brooklyn Borough President Eric Adams, NYC Health & Hospitals/Bellevue was motivated in November 2017 to develop the Plant-based Lifestyle Medicine Program, which offers patients with chronic diseases support services to transition to and stick with eating vegetarian. The public health system has invested $400,000 for the pilot program, which officially kicks off Jan. 16 with more than 300 patients.

Strategies

Conduct a full medical assessment of patients, including their lifestyle goals and medications they take.
Hire a health coach and dietitian to support patients in their transition to a vegetarian diet.
Physicians should meet with patients routinely to discuss progress as well as challenges and adjust medications.
Interest in the program is much higher than the hospital expected. The pilot—and funding—was originally designed for 100 patients. “Now that we have seen the response, we are going to do our best to reach as many patients through the funding period,” said Dr. Michelle McMacken, an internist at the health system and director of the program.
The pilot period is slated to run until October. Only patients with Type 2 diabetes, pre-diabetes, high blood pressure, high cholesterol, excess weight or heart disease can participate. Patients with those conditions were targeted because that’s where evidence most strongly shows plant-based diets can help reverse or lower severity.
Through the funding, NYC Health & Hospitals hired a full-time health coach and dietitian. Four physicians, including McMacken, are also part of the program.
Initially, physicians will conduct a full medical assessment of each patient, including a discussion of disease history and drug regimen. They’ll also review the patient’s personal health goals and any social barriers that could hinder participation. The physician, health coach and dietitian then create a plan tailored for the patient’s specific needs.
McMacken said it will depend on each patient, but they will likely meet with a doctor every two months to review progress in the program and to determine if any medications can be adjusted or stopped. “I’ve found in my personal experience when patients change their diet explicitly to a plant-based diet they require fewer medications,” she said.
Patients will likely meet or speak on the phone with the health coach and dietitian every two weeks. Both the coach and dietitian are trained chefs, so they can provide recipes and offer cooking classes to patients, keeping in mind patients’ cultural preferences and financial barriers.
McMacken said the program will focus on affordable healthy food options like lentils, beans, chickpeas and root vegetables. Although McMacken was unable to provide the insurance makeup of the 300 participants, Bellevue has a large Medicaid population. The program can be covered by insurance. For uninsured patients, payment is arranged on a sliding fee scale based on income.
One participant, Arlene Marie Karole, 53, is eager to have additional support as she tries to eat healthier. Karole was diagnosed with breast cancer in 2015 and although she’s in remission, it was a wake-up call to make lifestyle changes. She learned about the program through Twitter. “I’m looking forward to the coaching,” she said. “It’s very different to have a coach, someone working with you, taking your blood work.” Karole said she would like to lose 30 pounds.
Along with helping patients change their diet, the health coach will also focus on other lifestyle issues like sleep habits, stressors, physical activity and smoking.
McMacken said the program was designed in part by looking at practices at other hospitals. A growing number of facilities have adopted similar programs, including Barnard Medical Center in Washington, D.C. It conducted National Institutes of Health-funded clinical trials, one of which found Type 2 diabetes patients on a vegan diet were more likely to reduce the need for medications than other patients. “I have no doubt that whatever (outcomes) Bellevue is looking to meet, it will,” said Susan Levin, a Barnard dietitian.
To test the program’s effectiveness, McMacken will monitor how participants’ clinical outcomes change, including blood pressure, blood sugar and weight loss. The long-term feasibility of the program and barriers to effective execution will be examined as well.

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Catholic Health Initiatives to sell Arkansas insurance plan to Centene


Years since it first announced it wanted to exit the insurance business, Catholic Health Initiatives is selling its Arkansas insurance plan QualChoice to health insurer Centene Corp.
The companies have not yet disclosed any terms of the deal, which must be approved by regulators. The deal includes QCA Health Plan and QualChoice Life and Health Insurance Co., owned by parent company QualChoice Holdings.
A CHI spokesman was unable to provide a comment, and Centene did not respond. The Arkansas Democrat-Gazette first reported the news Friday.
Not-for-profit CHI has been trying to shed its consolidated insurance division QualChoice Health, formerly called Prominence Health, for several years. QualChoice operated plans in seven states. CHI acquired the Little Rock-based commercial health plan Qualchoice Holdings in 2014, but in May 2016 announced it wanted to get out of the insurance business altogether after struggling to turn a profit. 
That year, CHI reported its consolidated insurance business experienced an operating loss before interest, depreciation and amortization of $85.4 million. While looking for buyers, CHI managed to improve QualChoice’s operating performance, reporting the subsidiary had a positive operating EBIDA before restructuring, impairment and other losses of $8.6 million in the fiscal year ended June 30, 2018. CHI’s operating EBIDA was $892.2 million and its net income totaled $222.1 million in 2018.
CHI said in its annual report published in September 2018 that it had entered into a nonbinding letter of intent to sell QualChoice’s commercial operations in Arkansas, though it didn’t name the potential buyer at the time. CHI sold its Medicare Advantage contract in Washington to Premera Blue Cross in 2018.
St. Louis-based Centene mostly handles Medicaid and ACA exchange plans. Its net income totaled $828 million in 2017. A week ago, Centene announced it bought another big stake in the University Hospital of Torrejon de Ardoz in Madrid, Spain, bringing its total stake in the hospital to 89%.
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DNA design that anyone can do


Researchers at MIT and Arizona State University have designed a computer program that allows users to translate any free-form drawing into a two-dimensional, nanoscale structure made of DNA.
Until now, designing such structures has required technical expertise that puts the process out of reach of most people. Using the new program, anyone can create a DNA nanostructure of any shape, for applications in cell biology, photonics, and quantum sensing and computing, among many others.
“What this work does is allow anyone to draw literally any 2-D shape and convert it into DNA origami automatically,” says Mark Bathe, an associate professor of biological engineering at MIT and the senior author of the study.
The researchers published their findings in the Jan. 4 issue of Science Advances, and the program, called PERDIX, is available online. The lead authors of the paper are Hyungmin Jun, an MIT postdoc, and Fei Zhang, an assistant research professor at Arizona State University. Other authors are MIT research associate Tyson Shepherd, recent MIT PhD recipient Sakul Ratanalert, ASU assistant research scientist Xiaodong Qi, and ASU professor Hao Yan.
Automated design
DNA origami, the science of folding DNA into tiny structures, originated in the early 1980s, when Ned Seeman of New York University proposed taking advantage of DNA’s base-pairing abilities to create arbitrary molecular arrangements. In 2006, Paul Rothemund of Caltech created the first scaffolded, two-dimensional DNA structures, by weaving a long single strand of DNA (the scaffold) through the shape such that DNA strands known as “staples” would hybridize to it to help the overall structure maintain its shape.
Others later used a similar approach to create complex three-dimensional DNA structures. However, all of these efforts required complicated manual design to route the scaffold through the entire structure and to generate the sequences of the staple strands. In 2016, Bathe and his colleagues developed a way to automate the process of generating a 3-D polyhedral DNA structure, and in this new study, they set out to automate the design of arbitrary 2-D DNA structures.
To achieve that, they developed a new mathematical approach to the process of routing the single-stranded scaffold through the entire structure to form the correct shape. The resulting computer program can take any free-form drawing and translate it into the DNA sequence to create that shape and into the sequences for the staple strands.
The shape can be sketched in any computer drawing program and then converted into a computer-aided design (CAD) file, which is fed into the DNA design program. “Once you have that file, everything’s automatic, much like printing, but here the ink is DNA,” Bathe says.
After the sequences are generated, the user can order them to easily fabricate the specified shape. In this paper, the researchers created shapes in which all of the edges consist of two duplexes of DNA, but they also have a working program that can utilize six duplexes per edge, which are more rigid. The corresponding software tool for 3-D polyhedra, called TALOS, is available online and will be published soon in the journal ACS Nano. The shapes, which range from 10 to 100 nanometers in size, can remain stable for weeks or months, suspended in a buffer solution.
“The fact that we can design and fabricate these in a very simple way helps to solve a major bottleneck in our field,” Bathe says. “Now the field can transition toward much broader groups of people in industry and academia being able to functionalize DNA structures and deploy them for diverse applications.”
Nanoscale patterns
Because the researchers have such precise control over the structure of the synthetic DNA particles, they can attach a variety of other molecules at specific locations. This could be useful for templating antigens in nanoscale patterns to shed light on how immune cells recognize and are activated by specific arrangements of antigens found on viruses and bacteria.
“How nanoscale patterns of antigens are recognized by immune cells is a very poorly understood area of immunology,” Bathe says. “Attaching antigens to structured DNA surfaces to display them in organized patterns is a powerful way to probe that biology.”
Another key application is designing light-harvesting circuits that mimic the photosynthetic complexes found in plants. To achieve that, the researchers are attaching light-sensitive dyes known as chromophores to DNA scaffolds. In addition to harvesting light, such circuits could also be used to perform quantum sensing and rudimentary computations. If successful, these would be the first quantum computing circuits that can operate at room temperature, Bathe says.
Story Source:
Materials provided by Massachusetts Institute of Technology. Original written by Anne Trafton. Note: Content may be edited for style and length.
Journal Reference:
  1. Hyungmin Jun, Fei Zhang, Tyson Shepherd, Sakul Ratanalert, Xiaodong Qi, Hao Yan, Mark Bathe. Autonomously designed free-form 2D DNA origami. Science Advances, 2019; 5 (1): eaav0655 DOI: 10.1126/sciadv.aav0655
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Baird Starts AVEO Pharmaceuticals (AVEO) at Outperform


Baird analyst Madhu Kumar initiates coverage on AVEO Pharmaceuticals (NASDAQ: AVEO) with a Outperform rating

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