The boom in mini stomachs, brains, breasts, kidneys and more

Biologists are building banks of 'organoids', and learning a lot about human development on the way.

• Cassandra Willyard 29 July 2015

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Illustrations by Claire Welsh/Nature

It was an otherwise normal day in November when Madeline Lancaster realized that she had accidentally grown a brain. For weeks, she had been trying to get human embryonic stem cells to form neural rosettes, clusters of cells that can become many different types of neuron. But for some reason her cells refused to stick to the bottom of the culture plate. Instead they floated, forming strange, milky-looking spheres.

“I didn't really know what they were,” says Lancaster, who was then a postdoc at the Institute of Molecular Biotechnology in Vienna. That day in 2011, however, she spotted an odd dot of pigment in one of her spheres. Looking under the microscope, she realized that it was the dark cells of a developing retina, an outgrowth of the developing brain. And when she sliced one of the balls open, she could pick out a variety of neurons. Lancaster realized that the cells had assembled themselves into something unmistakably like an embryonic brain, and she went straight to her adviser, stem-cell biologist Jürgen Knoblich, with the news. “I've got something amazing,” she told him. “You've got to see it.”

Lancaster and her colleagues were not the first to grow a brain in a dish. In 2008, researchers in Japan reported¹that they had prompted embryonic stem cells from mice and humans to form layered balls reminiscent of a cerebral cortex. Since then, efforts to grow stem cells into rudimentary organs have taken off. Using carefully timed chemical cues, researchers around the world have produced three-dimensional structures that resemble tissue from the eye, gut, liver, kidney, pancreas, prostate, lung, stomach and breast. These bits of tissue, called organoids because they mimic some of the structure and function of real organs, are furthering knowledge of human development, serving as disease models and drug-screening platforms, and might eventually be used to rescue damaged organs (see ‘The organoid bank’). “It's probably the most significant development in the stem-cell field in the last five or six years,” says Austin Smith, director of the Wellcome Trust/MRC Stem Cell Institute at the University of Cambridge, UK.

The current crop of organoids isn't perfect. Some lack key cell types; others imitate only the earliest stages of organ development or vary from batch to batch. So researchers are toiling to refine their organoids — to make them more complex, more mature and more reproducible. Still, biologists have been amazed at how little encouragement cells need to self-assemble into elaborate structures. “It doesn't require any super-sophisticated bioengineering,” says Knoblich. “We just let the cells do what they want to do, and they make a brain.”

Growing a gut

This shouldn't come as a major surprise, says molecular biologist Melissa Little at the University of Queensland, Australia. “The embryo itself is incredibly able to self-organize; it doesn't need a template or a map.” That has been known since the early 1900s, when embryologists showed that sponges that had been broken up into single cells could reassemble themselves. But such work fell out of fashion, and modern biologists have focused their attention on purifying cells and growing them in culture — often in flat layers that do little to mimic normal human tissue.

Studying these cells to understand how an organ functions is like studying a pile of bricks to understand the function of a house, says Mina Bissell, a cancer researcher at the Lawrence Berkeley National Laboratory in California. “We should just begin to make the house,” she says. Bissell's work on cultures of breast cells helped to propagate the idea that cells behave differently in 3D cultures than in conventional flat ones. By the mid-2000s, the idea was catching on. The burst of enthusiasm was fuelled by Yoshiki Sasai, a stem-cell biologist at the RIKEN Center for Developmental Biology in Kobe, Japan, who turned heads when he grew a cerebral cortex¹, followed by a rudimentary optic cup² and pituitary gland³ (see Nature 488, 444–446; 2012).

Just a year after Sasai announced his layered cortex, Hans Clevers, a stem-cell researcher at the Hubrecht Institute in Utrecht, the Netherlands, reported the creation of a mini-gut⁴. The breakthrough stemmed from a discovery in 2007, when Clevers and his colleagues had identified intestinal stem cells in mice. In the body, these cells seemed to have an unlimited capacity to divide and replenish the intestinal lining, and one of Clevers' postdocs, Toshiro Sato, was tasked with culturing them in the lab.

Related stories

• ‘Organs-on-chips’ go mainstream
• Tissue engineering: Organs from the lab
• Q&A: Hans Clevers

More related stories

Rather than growing the cells flat, the pair decided to embed them in matrigel, a soft jelly that resembles the extracellular matrix, the mesh of molecules that surrounds cells. “We were just trying things,” Clevers says. “We hoped that we would make maybe a sphere or a blob of cells.” Several months later, when Clevers put his eye to Sato's microscope, he saw more than blobs. The cells had divided, differentiated into multiple types, and formed hollow spheres that were dotted with knobby protrusions. Inside, the team found structures that resembled the intestine's nutrient-absorbing villi as well as the deep valleys between them called crypts. “The structures, to our total astonishment, looked like real guts,” Clevers says. “They were beautiful.”

The mini-guts, reported in 2009, may prove to be a powerful tool in personalized medicine. Clevers and his team are using them to study the effectiveness of drugs in people with cystic fibrosis, who have genetic defects that affect ion channels and disrupt the movement of water in and out of the cells lining the lungs and intestine. The researchers take rectal biopsies from people with the disease, use the cells to create personalized gut organoids and then apply a potential drug. If the treatment opens the ion channels, then water can flow inwards and the gut organoids swell up. “It's a black-and-white assay,” Clevers says, one that could prove quicker and cheaper than trying drugs in people to see whether they work.

He has already used the system to assess whether a drug called Kalydeco (ivacaftor), and 5 other cystic-fibrosis drugs, will work in about 100 patients; at least 2 of them are now taking Kalydeco as a result.

Organoids may also help physicians to choose the best therapies for people with cancer. Earlier this year, Clevers revealed that he had grown a bank of organoids from cells extracted from colorectal tumours⁵, and David Tuveson, a cancer researcher at Cold Spring Harbor Laboratory in New York, worked with Clevers to generate pancreas organoids using biopsies taken from people with pancreatic cancer⁶. In both cases, the organoids could be used to find drugs that work best on particular tumours. “What patients are looking for is a logical approach to their cancer,” Tuveson says. “I'm very excited about what we're learning.”

The organoid bank

Since the late 2000s, biologists have grown a wide variety of rudimentary organs to understand development and for medical uses.

Organoid	Potential application
Cerebral cortex	Understand brain development as well as neurodegenerative diseases and other disorders
Intestine	Personalized organoids for identifying patient-tailored drugs
Optic cup	Source of retinal tissue for eye therapies
Pituitary gland	Source of therapeutic cells for endocrine disorders
Kidney	Toxicity testing and a source of tissue for transplantation
Liver	Repair of damaged liver
Pancreas	Treat diabetes and identify drugs for pancreatic cancer
Neural tube	Study nerve development and a source of cell therapies
Stomach	Understand stomach development and model gastric disorders such as ulcers
Prostate	Predict effective drug combinations for prostate cancer
Breast	Understand tumour development
Heart	Study cardiac development and how drugs affect it
Lung	Model for lung development, maturation and disease

More

The small-scale stomach

That excitement is shared by developmental biologist James Wells, who last year reported that he and his team had created an organoid that resembled part of a human stomach⁷.

Wells started with a different raw material to Clevers, whose organoids arise from adult stem cells that can generate only a limited number of cell types. Wells, who is at the Cincinnati Children's Hospital Medical Center in Ohio, and his colleagues craft organoids from embryonic stem cells, which have the ability to become almost any type of cell. As a result, they have been able to create mini-organs that are more complex.

A decade ago, Wells and his colleagues began trying to coax human embryonic stem cells to form intestinal cells. When the team manipulated two key signalling pathways, the layer of cells produced tiny round buds. Wells noticed that these 'spheroids' mimicked sections of the primitive gut tube, which forms four weeks after conception. This was thrilling, because he realized that he now had a starting point from which to develop a variety of organoids. “Every organ from your mouth down to your anus — oesophagus, lungs, trachea, stomach, pancreas, liver, intestine, bladder — all of them come from this very primitive tube,” he says.

Wells and his colleagues mined the literature and their own experience to determine what chemical cues might send these gut tubes down the developmental path toward a specific organ. Using this strategy, in 2011 the team developed its first human organoid⁸, an intestine about the size of a sesame seed. But growing a stomach was a bigger challenge. In humans, the organ has two key areas: the fundus at the top, which churns out acid, and the antrum towards the base, which produces many key digestive hormones — and the signalling pathways that lead to one versus the other were unknown. What is more, “the human stomach is different from the stomachs of most animals that we use in the lab”, so there is no good animal model, says Kyle McCracken, a former graduate student of Wells and now a medical student at the centre.

The researchers went for a trial-and-error approach: they made some educated guesses and painstakingly tested different combinations of growth factors. Eventually, the effort paid off. In a 2014 paper⁷, Wells and his team revealed that they had created organoids that resembled the antrum. Using these as a model system, the team says that it has figured out the chemical trigger that prompts the development of a fundus. Now the researchers are working to answer other basic questions about stomach development and physiology, such as which factors regulate acid secretion, and they are trying to generate other mini-organs from their primitive gut tubes.

This newfound ability to examine human development excites Daniel St Johnston, a developmental geneticist at the University of Cambridge's Gurdon Institute. “You can actually watch how the cells organize themselves to make complicated structures,” he says — something that is impossible in a human embryo. But most organoids are still single tissues, which limits what developmental biologists can learn, he says. “There are certain questions you can't really address because they depend upon the physiology of the whole organism.”

The baby kidney

Melissa Little has spent more than a decade marvelling at the complexity of the kidney. “It has, in an adult, probably 25–30 different cell types, each doing different jobs,” she says. Tubular structures called nephrons filter fluid from the blood and produce urine. The surrounding space, called the interstitium, holds an intricate network of blood vessels and the plumbing that carries urine away.

In 2010, Little and her colleagues started trying to turn embryonic stem cells into a progenitor cell that gives rise to nephrons. For three years, they tried various combinations and timings of growth factors. “It really took a lot of mucking around to make progress,” she says. But finally, in 2013, the team landed on just the right mixture. Little had been aiming to produce just the progenitor cells. But when she looked in the dish she saw two cell types spontaneously patterning themselves as they would in an embryo. “There was a moment of, 'Oh wow. Isn't that amazing',” she says.

This organoid resembles an embryonic kidney rather than an adult one: it has a mix of nephron progenitors and the cells that give rise to urine-collecting ducts⁹. “If you want to get them to mature further, that's where the challenge really lies,” Little says. So her team has been working to grow a more-sophisticated version — with blood vessels and interstitium. The hope then is to transplant the mini-organs into mice to see if they will mature and produce urine. “I'm pretty excited about what we can build,” Little says.

Because the kidney plays a key part in drug metabolism and excretion, Little thinks that her mini-kidneys could be useful for testing drug candidates for toxicity before they reach clinical trials. And researchers say that other human organoids, such as heart and liver, could similarly be used to screen drug candidates for toxic effects — offering a better read-out on the response of an organ than is possible with standard tissue culture or animal testing.

But Michael Shen, a stem-cell researcher at Columbia University in New York who has created a prostate organoid, is sceptical that these model systems could completely replace lab animals. Animals can show how a therapy affects the immune system, for example, something that organoid systems cannot currently do. “You want to be able to validate your experimental findings in an in vivo system,” he says. “I view that as a rigorous test.”

Little livers

Takanori Takebe was inspired to grow a liver after a chilling spell in New York. While working in the organ-transplantation division at Columbia University in 2010, Takebe saw people die from liver failure owing to a lack of organs. “That was a sad situation,” he says. When he looked into tissue engineering, he thought that the usual methods — seeding cells onto an artificial scaffold — seemed destined to fail. Part of the problem, he says, is that adult liver cells are very difficult to grow. “We cannot maintain it in culture for even a couple of hours.”

Takebe, who took up a research position at Yokohama City University in Japan, decided to work on induced pluripotent stem (iPS) cells, adult cells that have been reprogrammed to behave like embryonic stem cells. He coaxed human iPS cells into forming liver-cell precursors, or hepatoblasts. In the embryo, hepatoblasts rely on a complex symphony of signals from other nearby cells to mature, and Takebe suspected that these support cells would also be necessary to develop a liver in a dish. He and his colleagues mixed hepatoblasts with such cells — called mesenchymal and endothelial cells — and it worked. The team managed to create 'liver buds', structures no bigger than a lentil that resemble the liver of a six-week-old human embryo¹⁰. The researchers went on to find that, unlike mature liver cells, such structures can survive in culture for as long as two months.

A liver bud is still a far cry from an entire liver — a hefty, multi-lobed organ composed of tens of billions of hepatocytes. But Takebe hopes that if he can infuse many thousands of buds into a failing organ, he might be able to rescue enough of its function to make a transplant unnecessary. The process seems to work in mice. When Takebe and his group transplanted a dozen of the buds into mouse abdomens, they saw dramatic effects. Within two days, the buds had connected up with the mouse's blood supply, and the cells went on to develop into mature liver cells that were able to make liver-specific proteins and to metabolize drugs. To mimic liver failure, the team wiped out the animals' natural liver function with a toxic drug. After a month, most of the control mice had died, but most of those that received liver bud transplants had survived.

Takebe and his team hope to start human trials in four years. “We will target the children that critically need a liver transplant,” he says. He and his colleagues are currently working to make the liver buds smaller and produce them in huge quantities that they can infuse through the large portal vein that feeds the liver. Takebe thinks that the timeline is “doable”. But Smith says that the process seems rushed, and that the basic biology of these organs needs to be well understood before they are used in the clinic. “It's like running before you can walk,” he says.

Biologists know that their mini-organs are still a crude mimic of their life-sized counterparts. But that gives them something to aim for, says Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina. “The long-term goal is that you will be able to replicate more and more of the functionality of a human organ.” Already, the field has brought together developmental biologists, stem-cell biologists and clinical scientists. Now the aim is to build more-elaborate organs — ones that are larger and that integrate more cell types.

And Wells says that even today's rudimentary organoids are facilitating discoveries that would have been difficult to make in an animal model, in which the molecular signals are hard to manipulate. “In a Petri dish it's easy,” he says. “We have chemicals and proteins that we can just dump onto these cells.”

Nature

 

523,

 

520–522

 

(30 July 2015)

 

doi:10.1038/523520a

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Chinese factory replaces 90% of humans with robots, production Soars

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INNOVATION

Chinese factory replaces 90% of humans with robots,

production soars

Changying Precision Technology Company in Dongguan city has set up

an unmanned factory run almost entirely by robots. The factory has since
 seen a fewer defects and a higher rate of production. 

By Conner Forrest July 30, 2015, 11:30 AM PST //  connerforrest

• RSS

 Image: iStockphoto/06photo

The gravest fear that has rippled through humanity from the technology industry is that, someday, almost all of our jobs will be replaced by robots.

While that fear is often laughed off as something that will only happen far into the future, the truth is that it's actually happening right now.

In Dongguan City, located in the central Guangdong province of China, a technology company has set up a factory run almost exclusively by robots, and the results are fascinating.

The Changying Precision Technology Company factory in Dongguan has automated production lines that use robotic arms to produce parts for cell phones. The factory also has automated machining equipment, autonomous transport trucks, and other automated equipment in the warehouse.

There are still people working at the factory, though. Three workers check and monitor each production line and there are other employees who monitor a computer control systems. Previously, there were 650 employees at the factory. With the new robots, there's now only 60. Luo Weiqiang, general manager of the company, told the People's Daily that the number of employees could drop even further to 20 in the future.

The robots have produced almost three times as many pieces as were produced before. According to the People's Daily, production per person has increased from 8,000 pieces to 21,000 pieces. That's a 162.5% increase.

The increased production rate hasn't come at the cost of quality either. In fact, quality has improved. Before the robots, the product defect rate was 25%, now it is below 5%.

Shenzhen Evenwin Precision Technology, also based in Dongguan, announced a similar effort in May 2015. This region of China if often referred to as the "world's workshop" due to the high number of factories located there.

The shift happening with automation has been in the works for many similar companies in the area for quite some time. Foxconn, the controversial manufacturer of many gadgets such as the iPhone and iPad announced its robot initiative back in 2011.

Dongguan is about an hour's car ride north of Shenzhen, which is widely regarded as the one of the top regions in the world for gadget manufacturing. The growth of robotics in the area's factories comes amidst a particularly harsh climate around factory worker conditions, highlighted by strikes in the area. One can only wonder whether automation will add fuel to the fire or quell some of the unrest.

Some of the influx of robotics in the region is due to the Made in China 2025 initiative, and we will continue to see automation affect the area and potentially reduce the number of manufacturing jobs. Additionally, in March, 2015, the Guangdong government announced a three year plan to increase automation in the region by subsidizing the purchase of robots.

According to the International Federation of Robotics (IFR), electronics production was one of the biggest growth drivers for the sales of industrial robots. China was the largest market for industrial robotics in 2014 with nearly 60,000 robots sold.

Mammograms Again Found to Have No Impact on Mortality

July 28, 2015 | l

Do annual mammograms save lives?

Several studies over the past few years have concluded that mammograms do not save lives, and may actually harm more women than they help, courtesy of false positives, overtreatment, and radiation-induced cancers.

According to research1 published in 2010, the reduction in mortality as a result of mammographic screening was so small as to be nonexistent — a mere 2.4 deaths per 100,000 person-years were spared.

Another study2 published in The Lancet Oncology in 2011 demonstrated, for the first time, that women who received the most breast screenings had a highercumulative incidence of invasive breast cancer over the following six years than the control group who received far less screenings.Now, researchers from Harvard and Dartmouth have published a paper3 in which they present similar conclusions.

Mammograms Have No Impact on Breast Cancer Mortality

After analyzing cancer registry data from 16 million women in 547 counties across the United States, they found “no evident correlation between the extent of screening and 10-year breast cancer mortality.”

The researchers concluded that mammograms primarily find small, typically harmless, or non-lethal tumors, leading to widespread overdiagnosis.

As explained by Dr. Otis Webb Brawley, chief medical officer of the American Cancer Society and author of the book, How We Do Harm, the term "overdiagnosis" in cancer medicine refers to:

"...a tumor that fulfills all laboratory criteria to be called cancer but, if left alone, would never cause harm. This is a tumor that will not continue to grow, spread, and kill. It is a tumor that can be cured with treatment but does not need to be treated and/or cured."

Also, echoing results found in 2011, higher screening rates were associated with higher incidence of breast cancer. As reported by The LA Times:4

“For every 10-percentage-point increase in screening rates, the incidence of breast cancer rose by 16 percent... That worked out to an extra 35 to 49 breast cancer cases for every 100,000 women...

The researchers also examined breast cancers according to their stage at diagnosis, a marker of a tumor’s aggressiveness. More screening was associated with a higher incidence of early-stage breast cancers but no change for later-stage tumors, according to the study.

How can this be?

‘The simplest explanation is widespread overdiagnosis, which increases the incidence of small cancers without changing mortality,’ the study authors wrote. ‘Even where there are 1.8 times as many cancers being diagnosed, mortality is the same.’”

To Screen or Not to Screen?

Clearly, the issue of breast cancer screening using mammography can be a deeply emotional one. Virtually all discussions relating to cancer are. A recent article in Forbes Magazine5 paints a vivid picture of most women’s fears, and warns of the dangers of not getting diagnosed in time.

While it needs to be an individual choice, I believe it can be valuable to take a step back and look at the big picture, which includes population-based statistics such as those presented above.  

It’s also well worth investigating all available options and, of course, weigh the risks and benefits associated with each. As reported by Care2:6

“[The] study authors... point to a balance of benefits and harms and believe mammography is likely most favorable when directed at women who are at high risk — not too rarely and not too frequently.

They also believe watchful waiting, rather than immediate active treatment, is probably a good option in some cases.”

A main objection to mammography is the fact that it uses ionizing radiation to take images of your breasts, and it’s a well-established fact that ionizing radiation can cause cancer.

So the idea that the “best” way for you to avoid dying from cancer is to expose yourself to cancer-promoting radiation at regular intervals for decades on end (in order to catch the cancer early) really falls short on logic — especially since there are non-ionizing radiation imaging techniques available.

Results published in the British Medical Journal7 (BMJ) in 2012 show that women carrying a specific gene mutation called BRCA1/2 are particularlyvulnerable to radiation-induced cancer.

Women carrying this mutation who were exposed to diagnostic radiation before the age of 30 were twice as likely to develop breast cancer, compared to those who did not have the mutated gene.

They also found that the radiation-induced cancer was dose-responsive, meaning the greater the dose, the higher the risk of cancer developing. The authors concluded that:

“The results of this study support the use of non-ionizing radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.”

Mammograms Do Not Reduce Mortality Beyond That of Physical Examination

Last year, one of the largest and longest investigations into mammography was published.8

It involved 90,000 women who were followed for 25 years, and it sent shockwaves through the medical industry when it reported that the death rates from breast cancer were virtually identical among women who got annual mammograms and those who did not.

Moreover, it found that mammography screening had harmful effects. As reported by The New York Times:9

“One in five cancers found with mammography and treated was not a threat to the woman’s health and did not need treatment such as chemotherapy, surgery, or radiation.”

At the outset of the study, the women, aged 40-59, were randomly assigned to receive either five annual mammography screens, or an annual physical breast examination without mammography.Over the course of the study, 3,250 of the women who received mammography were diagnosed with breast cancer, compared to 3,133 in the non-mammography group. 

Of those, 500 women in the mammography group, and 505 in the control group, died from the disease. However, after 15 years of follow-up, the mammography group had another 106 extra cancer diagnoses, which were attributed to overdiagnosis. According to the authors:10

“Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Overall, 22 percent of screen detected invasive breast cancers were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.”

The rate of overdiagnosis (22 percent) is virtually identical to that found in a 2012 Norwegian study,11 which found that as many as 25 percent of women are consistently overdiagnosed with breast cancer that, if left alone, would cause no harm. Other studies that have come to similar conclusions include the following:

• In 2007, the Archives of Internal Medicine12 published a meta-analysis of 117 randomized, controlled mammogram trials. Among its findings: rates of false-positive results are high (20-56 percent after 10 mammograms)
• A 2009 meta analysis by the Cochrane Database review13 found that breast cancer screening led to a 30 percent rate of overdiagnosis and overtreatment, which increasedthe absolute risk of developing cancer by 0.5 percent.  The review concluded that for every 2,000 women invited for screening throughout a 10 year period, the life of just ONE woman was prolonged, while 10 healthy women were underwent unnecessary treatment.

Know the Signs and Symptoms of Breast Cancer

Mammograms can also miss the presence of cancer. According to the National Cancer Institute (NCI), mammograms miss up to 20 percent of breast cancers present at the time of screening. Your risk for a false negative is particularly great if you have dense breast tissue, and an estimated 49 percent of women do.14 Mammography's sensitivity for dense breasts is as low as 27 percent,15 which means that about 75 percent of dense-breasted women are at risk for a cancer being missed if they rely solely on mammography. Even with digital mammography, the sensitivity is still less than 60 percent.

Considering the mortality rate from breast cancer is virtually identical whether you get an annual mammogram or an annual physical breast exam, it suggests physical examination can go a long way toward detecting a potential cancer. It certainly makes sense to familiarize yourself with your breasts and the signs and symptoms of breast cancer.16,17 If you notice any of the following symptoms, be sure to address it with your doctor, even if you’re not due for an annual checkup yet.

Lump in the breast (keep in mind that breast lumps are common, and most are not cancerous)	Dimpling of the breast surface, and/or “orange peel” skin texture
Pain or unusual tenderness or swelling in the breast	Visible veins on the breast
Retracted nipple	Change in size or shape of the breast
Nipple discharge	Enlarged lymph nodes (located in the armpit)
Vaginal pain	Unintentional weight loss

Optimize Your Vitamin D for Breast Cancer Prevention

While detection and diagnosis of breast cancer is certainly important as early treatment has a greater chance of success,prevention is really key, and here you can wield a lot of power over your own destiny. In the largest review of research into lifestyle and breast cancer, the American Institute of Cancer Research estimated that about 40 percent of US breast cancer cases could be prevented if people made wiser lifestyle choices. I believe that is a very conservative estimate.

It’s likely that 75 percent to 90 percent of breast cancers could be avoided by strictly applying the recommendations below, especially when done in combination, as part of an overall healthy lifestyle. Optimizing your vitamin D level alone has been shown to reduce your chances of breast cancer by at least 50 percent and double your chances of surviving breast cancer should you receive a breast cancer diagnosis. 

Vitamin D influences virtually every cell in your body and is one of nature's most potent cancer fighters. It’s actually able to enter cancer cells and trigger apoptosis (cell death). Vitamin D also works synergistically with every cancer treatment I'm aware of, with no adverse effects. The average vitamin D level found in American breast cancer patients18 is 17 ng/ml, a far cry from a more optimal 40-50 ng/ml. 

So please, be sure to regularly monitor your vitamin D levels and take whatever amount of vitamin D3 you need to maintain a clinically relevant level. (Remember you also need vitamin K2 if you’re taking an oral vitamin D supplement instead of getting regular sun exposure.)

Sources

Other Breast Cancer Prevention Tips

Other important lifestyle considerations that can help reduce your chances of breast cancer include the following:

Eat REAL Food	A key dietary principle for optimal health and disease prevention is to eat real food. Choose fresh, organic, preferably locally growth foods. That also means avoiding all types of processed foods, which can contain any number of health harming ingredients, from refined sugar, processed fructose, genetically engineered ingredients, carcinogenic pesticides, and tens of thousands of food additives that have not been tested for safety. Refined sugar is detrimental to your health in general and promotes cancer. As a general guideline, limit your total fructose intake to less than 25 grams daily. If you have cancer or are insulin resistant, you would be wise to restrict it to 15 grams or less. Consider reducing your protein intake to one gram per kilogram of lean body weight. Replace the eliminated protein and carbs with high-quality fats, such as organic eggs from pastured hens, high-quality meats, avocados, and coconut oil. There's compelling evidence that aketogenic diet helps prevent and treat many forms of cancer. Also consider adding more cancer-fighting foods, herbs, and spices to your diet, such as broccoli. To learn more about how anti-angiogenetic foods fight cancer, please see our previous article: “Dramatically Effective New Natural Way to Starve Cancer and Obesity.”
Get plenty of natural vitamin A	Vitamin A may also play a role in helping prevent breast cancer.19 It's best to obtain it from vitamin A-rich foods, rather than a supplement. Your best sources are organic egg yolks, raw butter, raw whole milk, and beef or chicken liver. Beware of supplementing as there's some evidence that excessive vitamin A can negate the benefits of vitamin D. Since appropriate vitamin D levels are crucial for your health in general, not to mention cancer prevention, this means that it's essential to have the proper ratio of vitamin D to vitamin A in your body.  Ideally, you'll want to provide all the vitamin A and vitamin D substrate your body needs in such a way that your body can regulate both systems naturally. This is best done by eating colorful vegetables (for vitamin A) and by exposing your skin to appropriate amounts sunshine every day (for vitamin D).
Get sufficient amounts of iodine	Iodine is an essential trace element required for the synthesis of hormones, and the lack of it can also cause or contribute to the development of a number of health problems, including breast cancer. This is because your breasts absorb and use a lot of iodine, which they need for proper cellular function. Iodine deficiency or insufficiency in any of tissue will lead to dysfunction of that tissue, and tumors are one possibility.  However, there's significant controversy over the appropriate dosage, so you need to use caution here. There's evidence indicating that taking mega-doses, in the tens of milligram range may be counterproductive. One recent study suggests it might not be wise to get more than about 800 mcg of iodine per day, and supplementing with as much as 12-13 mg (12,000-13,000 mcgs) could potentially have some adverse health effects.
Nourish your gut	Optimizing your gut flora will reduce inflammation and strengthen your immune response. Researchers have found a microbe-dependent mechanism through which some cancers mount an inflammatory response that fuels their development and growth.  They suggest inhibiting inflammatory cytokines might slow cancer progression and improve the response to chemotherapy. Adding naturally fermented food to your daily diet is an easy way to prevent cancer or speed recovery. You can always add a high-quality probiotic supplement as well, but naturally fermented foods are the best.
Avoid xenoestrogens	Xenoestrogens are synthetic chemicals that mimic natural estrogens. They have been linked to a wide range of human health effects, including reduced sperm counts in men and increased risk of breast cancer in women. There are a large number of xenoestrogens, such as bovine growth hormones in commercial dairy, plastics like bisphenol-A (BPA), phthalates, and parabens in personal care products, and chemicals used in non-stick materials, just to name a few.
Avoid charring your meats	Charcoal or flame broiled meat is linked with increased breast cancer risk. Acrylamide — a carcinogen created when starchy foods are baked, roasted, or fried — has been found to increase breast cancer risk as well.
Avoid unfermented soy products	Unfermented soy is high in plant estrogens, or phytoestrogens, also known as isoflavones. In some studies, soy appears to work in concert with human estrogen to increase breast cell proliferation, which increases the chances for mutations and cancerous cells.
Drink a quart of organic green vegetable juice daily	Review my juicing instructions for more detailed information.
Get plenty of high quality animal-based omega-3 fats	Omega-3 deficiency is a common underlying factor for cancer.
Take curcumin	This is the active ingredient in turmeric and in high concentrations can be very useful in the treatment of breast cancer. It shows immense therapeutic potential in preventing breast cancer metastasis.20 To learn more about its use for the prevention of cancer, please see my interview with Dr. William LaValley.
Avoid drinking alcohol	Or at least limit your alcoholic drinks to one per day.
Improve your insulin and leptin receptor sensitivity	Eating a whole food diet low in added sugars is key. Exercising regularly will also promote optimal insulin and leptin sensitivity
Avoid wearing underwire bras	There is intriguing data suggesting metal underwire bras increase your breast cancer risk.
Avoid electromagnetic fields	Items such as electric blankets and cell phones can be particularly troublesome and increase your cancer risk. Definitely avoid stashing your phone in your bra as you go about your day.