Nanoyeast and Other Cell Envelope Compositions for Protein Studies and Biosensor Applications

ABSTRACT: Rapid progress in disease biomarker discovery has increased the need for robust detection technologies. In the past several years, the designs of many immunoaffinity reagents have focused on lowering costs and improving specificity while also promoting stability. Antibody fragments (scFvs) have long been displayed on the surface of yeast and phage libraries for selection; however, the stable production of such fragments presents challenges that hamper their widespread use in diag-nostics. Membrane and cell wall proteins similarly suffer from stability problems when solubilized from their native environment. Recently, cell envelope compositions that maintain membrane proteins in native or native-like lipid environment to improve their stability have been developed. This cell envelope composition approach has now been adapted toward stabilizing antibody fragments by retaining their native cell wall environ-ment. A new class of immunoaffinity reagents has been developed that maintains antibody fragment attachment to yeast cell wall. Herein, we review recent strategies that incorporate cell wall fragments with functional scFvs, which are designed for easy production while maintaining specificity and stability when in use with simple detection platforms. These cell wall based antibody fragments are globular in structure, and heterogeneous in size, with fragments ranging from tens to hundreds of nanometers in size. These fragments appear to retain activity once immobilized onto biosensor surfaces for the specific and sensitive detection of pathogen antigens. They can be quickly and economically generated from a yeast display library and stored lyophilized, at room temperature, for up to a year with little effect on stability. This new format of scFvs provides stability, in a simple and low-cost manner toward the use of scFvs in biosensor applications. The production and “panning” of such antibody cell wall composites are also extremely facile, enabling the rapid adoption of stable and inexpensive affinity reagents for emerging infectious threats. Click here to download

Label-free electrochemical detection of an Entamoeba histolytica antigen using cell-free yeast-scFv probes†

Inexpensive, simple and quick detection of pathogen antigens in human samples is a key global health objective. Limiting factors include the cost and complexity of diagnostic tests that utilize antibody probes. Herein, we present a method for label-free electrochemical detection of a protein from the enteric pathogen Entamoeba histolytica using cell-free yeast-embedded antibodylike fragments (yeast-scFv) as novel affinity reagents.
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Immunotherapy Drug Trials Show Severe Side Effects Are Common

A study published in 2010 found that ipilimumab — an immunotherapy drug that blocks cytotoxic T-lymphocyte antigen-4, used against advanced melanoma — caused severe side effects in nearly 20 percent of patients.

Another study published in 2015 found adverse events in 24 percent of patients receiving ipilimumab, and when used in combination with nivolumab, another immunotherapy drug, severe adverse reactions occurred more than half the time.

Despite that, the study, funded by Bristol-Myers Squibb, concluded that the combination therapy "had an acceptable safety profile."

Most recently, a study published this summer found 30 percent of patients receiving either pembrolizumab or nivolumab suffered "interesting, rare or unexpected side effects" from the treatment.

No less than 242 different side effects were noted in all, including skin, gastrointestinal, liver, endocrine and renal system effects, diabetes mellitus and pancreatitis. One-quarter of these reactions were severe or life-threatening and required hospitalization.

Novartis is now seeking approval for CTL109, a drug shown to be effective against pediatric B-cell acute lymphoblastic leukemia.6 In its phase 2 study, 82 percent of pediatric and young adult patients experienced complete remission.

However, for many the victory was short-lived. Six months later, 40 percent of them had relapsed. Some of the side effects were also severe. Fifteen percent of patients experienced grade 3 neurological and psychiatric events, including encephalopathy (abnormal brain function) and delirium.

Breakthrough Therapy Program Raises Stakes for Patients

The FDA's Breakthrough Therapy program (and the European PRIME) worsens the situation. By rushing approvals, toxicology research ends up lagging even further behind, which means more patients end up being used as guinea pigs without actually being enrolled in a formal study.

This is a particularly frightening prospect in light of the fact that drug developers are increasingly starting to look to vaccines (categorized as "biologicals" by the FDA) as the pharmaceutical product of choice for all sorts of ailments. Clearly, drug companies want vaccines to largely replace prescription drugs as a primary source of profit-making because there's no product liability in civil court when toxic vaccines cause serious brain and immune system damage, even if people die.

This month, Congress and the U.S. Supreme Court went one step further in giving the pharmaceutical industry a free pass when it comes to requiring drug companies to provide solid scientific evidence that experimental drugs and vaccines are effective and will not harm people before they are sold and used by millions of Americans.

After two years of influence peddling by more than 1,000 pharmaceutical industry lobbyists determined to lower FDA licensing standards, Congress passed the 21st Century Cures Act so that new drugs and vaccines can be fast-tracked to market without holding large clinical trials to prove safety and effectiveness.13

As for immunotherapy drugs, we're already seeing these treatments being put to use by oncologists who are completely unprepared to address the multitude of unusual side effects. As noted by Timmerman, the oncologist who lost a patient to flu-like symptoms:14 "If we had only known the power we had unleashed that was causing such a toll on her organ system, we might have saved her."

Out-of-Control Immune System Attacks Healthy Organs

The New York Times (NYT) recently published a very comprehensive article well worth the read that details the struggles of Chuck Peal, who took part in a melanoma study at Yale. He received the ipilimumab with nivolumab combination.

Seven weeks later, he developed acute-onset diabetes — a brand new form of type 1 diabetes, to be exact, associated with these kinds of immune-altering drugs.

Type 1 diabetes typically strikes during childhood, but these drug-induced cases involve older patients who very suddenly lose all of their insulin production.

As reported in the article: "He slipped in and out of consciousness, his blood pressure plummeted, his potassium levels soared and his blood sugar spiked to 10 times the normal level …

[He] spent 24 days in the hospital … First his pancreas failed, then his bowels inflamed and his kidneys became dysfunctional, and 'to top it off, he has a fever of 103 for which we can't find a source,' Dr. [Harriet] Kluger said in an interview during the crisis … Peal's body was attacking itself, a severe reaction by his immune system that was a side effect of a seemingly miraculous cancer treatment aimed at saving his life … [A]s their use grows, doctors are finding that they pose serious risks that stem from the very thing that makes them effective. An unleashed immune system can attack healthy, vital organs: notably the bowel, the liver and the lungs, but also the kidneys, the adrenal and pituitary glands, the pancreas and, in rare cases, the heart. Doctors at Yale believe immunotherapy is causing a new type of acute-onset diabetes, with at least 17 cases there so far, Mr. Peal's among them."

Immunotherapy for Cancer — This Lauded Breakthrough Is Far More Dangerous Than Advertised

Immunotherapy drugs are considered the latest and greatest breakthrough in conventional cancer treatment. Chimeric antigen receptor technology (CAR-T) has raised a great deal of hope, and an equal measure of concern.

CAR-T involves genetically reengineering a patient's immune cells to target tumor-associated antigens, thereby destroying the malignant cells.

Alas, while these therapies appear to be quite effective at attacking and destroying malignant cells, they can also take a toll on healthy tissues and organs, leaving many patients struggling for their lives, albeit for an entirely different reason.

There's also another important issue at stake here. CAR-T cell therapies such as the one developed by Novartis (see below) have been granted PRIME1 (Priority Medicine) status by the European Medicines Agency (EMA).

PRIME is similar to the Breakthrough Therapies program2 offered by the U.S. Food and Drug Administration (FDA). Both of these priority medicine programs aim to speed up approval of novel drugs in order to bring hope to patients for whom there is little or no hope.

While this is admirable, it's also a slippery slope that can end up affecting people with non-lethal diseases as well — people who are NOT quite as keen on playing Russian roulette with their health for a chance of survival.

Cancer as a Metabolic Disease

Cancer is largely a metabolic, not a genetic. disease, and not all treatments will work for all cancers. That said, I believe great strides will be made — even for hard-to-treat cancers — once the metabolic underpinnings of cancer become more widely recognized.

It is profoundly tragic that the current focus is to employ genetically engineered immune cells to combat cancer, unleashing what amounts to an uncontrolled cytokine storm in the body, when addressing cancer metabolism can be done without harmful side effects.

Two excellent books written on this topic are "Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer," by Thomas Seyfried, Ph.D.,15 and "Tripping Over the Truth: The Metabolic Theory of Cancer" by Travis Christofferson. Seyfried is one of the pioneers in the application of nutritional ketosis for cancer, a therapy based on the work of Dr. Otto Warburg, who received the Nobel Prize in Physiology or Medicine in 1931 for the discovery of metabolism of malignant cells.

These two books made so much sense to me that I wrote a practical how-to guide on how to help people make the transition to burning fat as your primary fuel, which is the precise metabolic shift most everyone needs in order to most effectively treat not only cancer, but also heart and neurodegenerative diseases. The book, "Fat for Fuel," will be out in May 2017.

Cancer as a Metabolic Disease

Cancer is largely a metabolic, not a genetic. disease, and not all treatments will work for all cancers. That said, I believe great strides will be made — even for hard-to-treat cancers — once the metabolic underpinnings of cancer become more widely recognized.

It is profoundly tragic that the current focus is to employ genetically engineered immune cells to combat cancer, unleashing what amounts to an uncontrolled cytokine storm in the body, when addressing cancer metabolism can be done without harmful side effects.

Two excellent books written on this topic are "Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer," by Thomas Seyfried, Ph.D.,15 and "Tripping Over the Truth: The Metabolic Theory of Cancer" by Travis Christofferson. Seyfried is one of the pioneers in the application of nutritional ketosis for cancer, a therapy based on the work of Dr. Otto Warburg, who received the Nobel Prize in Physiology or Medicine in 1931 for the discovery of metabolism of malignant cells.

These two books made so much sense to me that I wrote a practical how-to guide on how to help people make the transition to burning fat as your primary fuel, which is the precise metabolic shift most everyone needs in order to most effectively treat not only cancer, but also heart and neurodegenerative diseases. The book, "Fat for Fuel," will be out in May 2017.

Adult Leukemia Trial Put on Hold After Additional Deaths

Juno Therapeutics is working on an immunotherapy for adults with refractory B cell acute lymphoblastic leukemia.

Its phase 2 trial was recently placed on hold for the second time this year following the death of two patients who developed cerebral edema, just days after receiving their treatment.8 One of the patients was under the age of 30.

In July, the FDA ordered a clinical hold on the trial following the death of three patients. They too died from cerebral edema. As reported by CNN:9

"… [I]nvestigators pinpointed the likely culprit as the addition of fludarabine to the pre-conditioning regimen. Fludarabine is a chemotherapy drug used here as a one-time primer for treatment … in an effort to increase the effectiveness of the experimental therapy.

In this particular course of treatment, pre-conditioning consists of a heavy dose of chemotherapy to kill off existing cancer cells in order to give the new cancer-killing T-cells room to grow.

It's like hitting a reset button to restart the immune system. But an unforeseen interaction between fludarabine and genetically modified JCAR015 cells proved to be lethal."

The trial was given the green light to resume in August — this time without the use of fludarabine. Still, two patients are dead from the same exact problem as the initial three, suggesting the chemotherapy drug wasn't the problem after all.

Brad Loncar, founder of a cancer immunotherapy fund told STAT News10 that Juno was "going way too fast. It's just terrible. They've killed a couple of people, and it seems like, in part, it's because of the rush to judgment."

Playing With Fire

According to Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, the use of immunotherapies is a dangerous game. "We're playing with fire," he told the NYT, shortly after losing a female patient to the treatment's after-effects.

Weeks after the drug sent her cancer into remission, she suddenly developed cold and flu-like symptoms that quickly killed her. The real cause of death? A massive, out-of-control inflammatory response mounted by her altered immune system. As reported in the featured article: "With lives to be saved and billions of dollars to be made — $250,000 or more is the list price for a year of some regimens — not enough research has been done into the risks of the new therapies, said William Murphy, [Ph.D.,] a professor of dermatology at the University of California, Davis, who reviews immunotherapy-related grants for the government.

It is 'a massively understudied area,' Murphy said, adding: 'The No. 1 priority is anti-tumor effects. Everything else, however severe, is considered the price worth paying.'"

Indeed, according to Murphy, only three of the 500 research proposals he reviewed were focused on toxicity. We see the same problem in other drug and vaccine research as well. Drug developers are primarily interested in finding out if the drug works. Is it effective? However, if a drug is effective in treating the ailment at hand, yet kills the patient, what has been gained?

You Don't Need Drugs to Correct Dysfunctional Energy Metabolism

Warburg discovered that cancer is really caused by a defect in the cellular energy metabolism of the cell, primarily related to the function of the mitochondria (the little power stations within your cells). In my view, this information is the game changer that not only is the foundation for nearly all cancers but virtually every disease known to man, because at the core of most serious ailments you find mitochondrial dysfunction.

At present, the cancer industry is focusing on the downstream effects of the problem, which is why the "war on cancer" has been such a miserable failure. In my interview with Seyfried, he specifically critiqued immunotherapy, saying: "Personalized medicines, checkpoint inhibitors — all of these kinds of therapies are basically looking at downstream effects of the disease."

Checkpoint inhibitor is another name for CAR-T or immunotherapy drugs. As described by Dana-Farber Cancer Institute on their "Immune Checkpoint Inhibitor Definition" page,16 it's a descriptive term, as these drugs basically prevent cancer cells from using immune checkpoint molecules to hide and evade attack by immune system T cells. By making sure the T cells can recognize the cancerous cells as malignant, your immune system can successfully rid itself of the cancer — sometimes rather rapidly.

However, as we've just discussed, the effects can be severe and/or lethal. And if Seyfried and others who are studying the metabolic theory of cancer are correct, such trauma is entirely unnecessary. Many cancer recurrences are also likely due to the initial treatment.

On the other hand, when you view cancer as a metabolic disease, you can target and manage the disease without creating systemic toxicity. As explained by Seyfried, you do this by targeting the fuels the cancer cells are using, primarily glucose and glutamine.

"What we have to recognize ... is that if cancer is a mitochondrial metabolic disease and you get cancer because of mitochondrial failure in certain populations of cells and certain tissues, if you prevent your mitochondria from entering into this dysfunctional state ... [then] the probability of getting cancer is going to be significantly reduced.

To what percent? I would say a minimum of 80 percent. Cancer is probably, as I said in my book, one of the most manageable diseases that we know of ... Once you realize what cancer is, that it's a metabolic disease, you can take charge of those kinds of things."

By Dr. Mercola

I don't look like I have cancer, but I've had to learn to live with this incurable disease

I will never forget the words from the oncologist when I was first diagnosed with metastatic breast cancer.

"We can put out the flames but it will always smoulder," the doctor said.

"You will learn to live with cancer. You will have to overcome the stigma of cancer."

For a start, being diagnosed with breast cancer was a shock. It took me days to digest the proposed treatment strategy of chemo, double mastectomy and radiotherapy: aka "poison, slice and burn".

But then a week later, I was not prepared for an even bigger shock. Advanced, stage 4 metastatic breast cancer had spread to my skull, collar bone, ribs, spine, pelvis, femur and humerus — not many spare bones left.

I was dumbfounded. So was my mother, who had recently retired from oncology. If anyone was supposed to get breast cancer, she thought it was herself, not her healthy, fit, young daughter who had just been skiing for a month with her two children, aged 10 and 8.

We were absolutely gutted and shell-shocked. How long did I have? What could I do? How could I defy the odds? My mind went into a tailspin.

Stable is a great word

The prognosis flipped. Chemo or surgery were no longer viable options.

The strategy immediately changes from excavation to a more conservative approach to slow down further progression, to contain and stabilise the disease.

I have since learnt that stable is a great word. But at the time this seemed incongruous and hideous. What do you mean slow down? I want it out, so give me everything — let's just bomb it completely!

The reality and the enormity of the diagnosis hit hard.

Some individuals are fortunate to have significant regression but the "mets" always lurk. Typically they go to the bones, lungs, brain and/or liver but in no particular order.

This is where ongoing treatment becomes such a huge, complex challenge as no approach fits everyone.

Three days later I had my ovaries out. This cut off the fuel supply and was an easy decision where I had some control.

Knowing what to say

Most people struggle to pronounce metastatic, let alone understand what it means.

The bewildered look on the person's face normally says it all. "But you look so good and so healthy," they exclaim, offering words of encouragement on something that most of us just don't confront — our imminent mortality.

Even worse are the seemingly innocuous questions, such "so when will your treatment be over, love?" from people who work in oncology and should know better.

It is so incredibly frustrating that many of us believe all breast cancer is curable.

That if you are strong, determined and positive, then you can fight and overcome the cancer.

This is unfounded. True, a positive mindset helps maintain resilience but this does not prevent the cancer from killing you.

Resilience is just the start

Before my diagnosis I submitted a PhD that suggested that emotional resilience determines how we respond to everyday obstacles, be they big or small.

Cancer is a big challenge, metastatic is huge.

The vulnerability experienced in the initial months was excruciating — total loss of control and overwhelming fear.

Scans are intimidating. A robotic voice commands "breathe in now, hold, breathe out now". No please or thank you, just commands to obey.

There is a total sense of helplessness as you await the next set of results — to see if the cancer has spread further.

Conflicting advice doesn't help

The lack of congruent, coordinated support made me feel like I was drowning in the ocean. Why was there so much conflicting advice?

All the focus seemed to be on early breast cancer. Why not metastatic, too?

The sense of isolation just exacerbated the fear and sleepless nights. It was a nightmare from which I could not wake up.

Having cancer is like being pregnant — you are absolutely flooded with information. Some is better than others, but much of it unsolicited.

I was bombarded with weird and wonderful suggestions of "alternative therapies". Some made sense, some not at all.

So much conflicting advice is sometimes demoralising, sometimes funny and other times very intrusive. This is where the importance of mindfulness and meditation cannot be underestimated.

The wonders of a fatal diagnosis

I have experienced amazing moments of insight over the past year. It's amazing what a fatal diagnosis can do! Having metastatic breast cancer is a constant reminder of the precious moments which create meaning and context in our life, and our legacy.

Eighteen months on and my disease is relatively stable. That said, I had two total hip replacements in May and recent breast surgery to try to prevent further mutations of the cancer.

Acceptance and surrender are integral components to my overall wellbeing, along with exercise and the hormonal and oral, targeted chemo treatment.

The side effects are tolerable, except for the crippling fatigue that hits late afternoon.

Despite a fantastic armamentarium of drugs now available, much research is still needed to thwart this hideous and clever disease.

But it's more than that: along with more research we need better understanding from the community (and the medical community, too) about the different effects of cancer.

Not everyone looks like the stereotype of a cancer patient: the challenge of managing breast cancer goes well beyond the surface.

Common genetic fusion event may be associated with low-risk prostate cancer - ScienceDaily

A Gleason score provides information on how aggressive a prostate cancer is. It is calculated when a prostate needle biopsy specimen is examined under a microscope. Depending on how normal or abnormal the cancer looks, it is assigned a number from 1 to 5, with 5 being the most abnormal and most aggressive. Different areas of a tumor may have different patterns, and the two highest patterns are added together to give the Gleason score. Most prostate cancers are Gleason score 6 (composed entirely of pattern 3) and men with Gleason score 6 are considered at low risk of having their tumors progress.

Cheville explained that active surveillance is a common approach to caring for patients with prostate cancer with a Gleason score of 6. Men on active surveillance receive no treatment and are followed. Some of these men are later found to have clinically significant disease that requires treatment. Identifying a biomarker that, in addition to Gleason score, distinguishes men at increased risk for disease progression from those whose prostate cancer never becomes a clinically significant problem could help improve patient care, added Cheville.

To look for genetic biomarkers of clinically significant or insignificant disease, Cheville and colleagues used whole-genome mate pair sequencing to study gene fusions in prostate cancer tissue samples obtained from 133 patients who underwent a radical prostatectomy at the Mayo Clinic. The prostate cancers were divided into four groups: 53 low volume Gleason 6 tumors were classed as very low risk for progression; 26 high volume Gleason 6 tumors were classed as low risk for progression; 29 Gleason 7 tumors were classed as intermediate risk for progression; and 25 Gleason 8 or higher tumors were classed as high risk for progression.

The researchers detected TMPRSS2-ERG fusions in 45 percent of the prostate cancers analyzed, which is consistent with prior studies, according to Cheville. Fusions were detected in 43 percent, 49 percent, 52 percent, and 24 percent in the very-low risk, low-risk, intermediate-risk, and high-risk groups, respectively.

Among the 60 prostate cancers with TMPRSS2-ERG fusions, 39 had deleted the interstitial genes between TMPRSS2 and ERG during the fusion event and 21 had retained these genes. Eighteen of the 21 prostate cancers that had retained the interstitial genes during TMPRSS2-ERG gene fusion were in the very-low risk and low-risk groups.

Information on whether a patient went on to have a biochemical recurrence was available for 34 patients who had prostate cancer with a TMPRSS2-ERG gene fusion with interstitial gene deletion and 22 patients who had prostate cancer with a TMPRSS2-ERG gene fusion with interstitial gene retention. In univariate, but not multivariate, analysis, biochemical recurrence was significantly lower if the prostate cancer had a TMPRSS2-ERG gene fusion with interstitial gene retention compared with those that had interstitial gene deletion.

"Our data support results from other studies in that the presence or absence of a TMPRSS2-ERG gene fusion was not predictive of outcome," Cheville said. "But how the gene fusion formed was important; the retention of interstitial genes during the fusion event was more common in very-low risk and low-risk cancers, and there may be genes in this region that suppress or limit tumor growth. There is potential utility for determining the status of interstitial genes in stratifying men with prostate cancer into more well-defined risk groups, but this will require further study before it can be incorporated into clinical practice.

"The loss or retention of interstitial genes was tied closely to Gleason score, and we did not have enough cases to determine whether or not the type of fusion was an independent marker for biochemical recurrence," continued Cheville. "We need to look at many more samples and also look at patients with higher Gleason scores to determine the extent to which loss of interstitial genes is associated with disease progression."

According to Cheville, the main limitation of the study is the relatively small number of patients analyzed in each group.

Materials provided by American Association for Cancer Research. Note: Content may be edited for style and length.

FDA Proposing to Ease DTC Genetic Tests' Path to Market

The US Food and Drug Administration (FDA) is proposing to ease the approval process for direct-to-consumer genetic tests, saying that the diagnostics can increase consumer engagement in their health.

"In its consideration of [genetic health risk] tests, the FDA seeks to strike a balance that provides for an efficient pathway to bring these tests to consumers, without sacrificing the assurances offered by FDA oversight," said Commissioner Scott Gottlieb, MD, in a statement.

"As consumer interest in genetic risk information grows, opportunities are also expanding for the detection of additional genetic conditions and diseases that can help inform people of their medical risks," Dr Gottlieb said.

But, he noted, the agency is not overlooking the risks associated with the tests, "especially if they provide consumers with incorrect or misleading information that may be used to make health choices without considering the advice of a medical professional." A potential downside, said Dr Gottlieb: "Consider the consequences of a person who is told they're not at risk for coronary heart disease and incorrectly opts to forgo dietary changes or drugs that reduce their risk of heart attack and death."

The proposal comes on the heels of what the agency considers a positive experience with the first genetic health risk (GHR) tests — marketed by 23andMe — which were approved in April. That maker's GHR tests — which isolate DNA from saliva — provide genetic risk information, but can't determine an individual's overall risk of developing a disease or condition.

The agency on November 6 said in a final notice that, in the future, any new 23andMe tests would not have to be reviewed before marketing as long as the manufacturer followed a long list of requirements, or "special controls," including giving consumers detailed information about risk, genetic counseling, and testing methodology and results.

Special Controls

The FDA is proposing to allow other makers of GHR tests to be exempted from premarket review under certain conditions. If the proposal is made final, GHR test makers would have to get a one-time FDA review to ensure that they meet the agency's requirements, and would then be allowed to market future tests without further review.

The tests would be subject to the special controls, including requirements for assuring accuracy, reliability, and clinical relevance. The FDA will also dictate the type of studies and data needed to demonstrate performance.

The agency is proposing the same exemption from premarket reviews for total 25-hydroxyvitamin D mass spectrometry tests, endoscopic maintenance systems, ultraviolet water purifiers for medical use, and genital vibrators for therapeutic use.

The proposal to "reclassify" these diagnostics and devices is open for public comment until December 31, after which the agency will likely move to make it final.

In the meantime, the FDA also on November 6 gave final approval for exemptions from premarket approval for two diagnostics already on the market.

The Vitamin D 200M Assay for the Topaz System (AB Sciex) will now be able to market new versions without seeking FDA approval first, if it adheres to the special controls. The FDA said in the final order that it was taking this action because it had determined that there would be "a reasonable assurance of safety and effectiveness," and that it "will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens."

The FDA also issued a final order exempting 23andMe's Personal Genome Service Carrier Screening Test for Bloom syndrome from the premarket approval requirements, following through on its stated intention when it approved the diagnostic in 2015.