Although melding human DNA and tissue with electronic devices has long been considered the stuff of science fiction, Taiwan’s companies, government-supported research laboratories and business alliances are currently working hard to make that dream a reality. Their goal is not to create the super-human cyborgs seen in literature and film, however, but rather to improve human health.
Taiwan has become a frontrunner in developing biochips, an umbrella term for devices that connect integrated circuits to organic molecules or living tissue. On passive biochips, tiny sensor arrays produce a signal that is fed directly to a computer, while active chips employ semiconductors to assist with or perform signal transmission.
In the health field, biochips are revolutionizing the way diseases are diagnosed, as they can assist with DNA sequencing and detect genetic markers that indicate cancer, among other applications. “We are not trying to modify DNA; we use biochips to find out where there are genomic variations, how people are different and how cancer cells are different from normal cells,” says Johnsee Lee (李鍾熙), president of MDxTaiwan, an alliance of 14 Taiwanese enterprises devoted to molecular diagnostic fields. “We can use gene analysis for diagnosis, drug discovery, disease prevention, treatment selection and ultimately for personalized health care.” Lee formerly served as president of the government-supported Industrial Technology Research Institute (ITRI) in Hsinchu, northern Taiwan. ITRI has been a major force behind the development of biochips in Taiwan.
Global sales of biochips are still relatively insignificant, as the market for chips used for developing drugs, diagnosing disease, ensuring food safety, performing research and sequencing DNA was worth US$4.2 billion in 2012, according to ITRI’s Industrial Economics and Knowledge Center (IEK). That market is predicted to grow to US$5.9 billion in 2014, however, and analysts have little doubt that new biochip technologies will see the sector double in size several times over the next decade.
Next Gold Rush
Gene sequencing was famously declared “The next [US]$100 billion technology business” by American business magazine Forbes in 2011 and biochips capable of identifying thousands or millions of genes at a time are expected to be the driving force behind that anticipated gold rush. It currently costs about US$8,000 to decode the genome of an individual human being, however, and the computer systems used in the effort typically come in the size of a dozen or so extra-large refrigerators. In 2006, Crackerbio, an ITRI spinoff, launched an effort to reduce the cost and complexity of DNA sequencing. Central to that project is Crackerbio’s development of a system that includes an improved semiconductor-based chip and a computer only the size of an ordinary laptop. The company’s system does not require massive computing power because the chip, which is made by Taiwan Semiconductor Manufacturing Co., does most of the work.
DNA contains the biological molecules adenine, cytosine, guanine and thymine, which are known as bases. The order of the bases creates the unique genetic code found in each living organism. There are numerous techniques used to sequence DNA; Crackerbio’s chip, which is expected to go on the market by 2016, does so with millions of tiny “wells” filled with enzymes. After an individual’s DNA sample is loaded in the device, the DNA reacts with the enzyme wells. Laser light is then directed at the wells, which causes each of the four bases to fluoresce with a different color. The colors are read by a sensor on the chip and their order is determined by the sequencer.
Johnsee Lee is president of MDxTaiwan, an alliance of 14 enterprises working in the biochip field. (Photo by Jens Kastner)
“As millions of wells carry out DNA sequencing reactions simultaneously on the chip, a very large genome can be sequenced quickly and economically,” says Lee, who has been involved in Crackerbio’s development. “Like this, the dream that every individual can have his own genome sequenced is turning into reality, and a new era in health care is about to unfold.”
Crackerbio aims to develop a system that brings the cost of sequencing a complete human genome down to around US$1,000. The company believes such a low-cost, rapid-sequencing system will be useful for controlling pandemics, diagnosing cancer and screening babies for diseases that are treatable but can cause irreversible damage if they go undetected. Other likely uses include performing DNA analysis to detect unsafe foods and improve agricultural yields. “Now genetic decoding is only done by experts in research centers, but after the chip becomes a commercial product, it can be done cost-effectively and reliably in every lab and clinic, making the market bigger and bigger,” Lee says.
The MDxTaiwan chief is confident that commercialization will take place within three years as scheduled. “We have the patents, we are making good progress on the chip development, but we have to build the whole machine and carry out verification tests before starting mass production,” he says.
Lee’s MDxTaiwan alliance was founded in 2012 to facilitate joint marketing and integrate the capabilities of the 14 individual member companies. Integration of the firms is important because their capabilities can be combined to create products with a broad range of functions. Hospitals prefer versatile diagnostic devices, as purchasing a machine capable of performing a panel of tests—one that can screen children for five types of viruses at a time, for example—is more economical than buying five machines that each perform just a single test.
Built to Order
Another standout MDxTaiwan member is Hsinchu-based Phalanx Biotech Group, which has been manufacturing and selling high-density DNA sensor arrays, or microarrays, since 2006. Like Crackerbio, Phalanx is an ITRI spinoff. “Depending on what you want to study, Phalanx can provide a specific microarray chip for genes, one for diseases, one for rice and so on,” Lee says.
The foundation for Phalanx’s OneArray microarray is a glass slide measuring 2.5 centimeters by 7.6 centimeters. A special chemical coating containing tens of thousands of DNA probes is then bonded to the slide. Each of the probes is designed to detect a specific gene or gene part through a process called “hybridization,” in which the probes bond with the targeted genetic material. After hybridization is completed, the glass slide is put in a fluorescence scanner. Differences in fluorescence reveal the presence or absence of the targeted gene depending on whether the probes have succeeded in hybridizing with their genetic material, and that information can be used to draw physiological conclusions about a patient’s tissue sample. In the case of cancer, for example, cells that are undergoing metastasis fluoresce at a certain wavelength. By detecting such fluorescence, the system identifies patients who require a more thorough cancer screening. “Cancer radiation therapy and chemotherapy are very harmful,” explains Lee Sheng-wan (李聖婉), CEO of Phalanx. “That means both under-treating and over-treating must be avoided.”
The flagship of Phalanx’s product line is the CytoOneArray, a glass-based chip used for prenatal and postnatal tests that detect a staggering 305 genetic diseases known to cause developmental delays and intellectual disabilities. While each tested disease or disorder is relatively rare, taken together they have a significant impact on human health. Only about 1 percent of the members of a given population suffer from autism, for example, but the combined percentage of those suffering from one of the 305 diseases on the CytoOneArray target list ranges from 6 percent to 8 percent.
Phalanx employees make OneArray biochips at a plant in Hsinchu, northern Taiwan. (Photo Courtesy of Phalanx Biotech Group)
“The best time for treatment that controls autism is usually between the ages 3 and 6, during the preschool years,” Lee Sheng-wan says of the medical rationale for tests. “Because once an autistic child starts school and displays behavior problems nobody understands, it creates severe social tension in the classroom and the family.”
Phalanx’s competitive advantage lies in a unique production technique with the lengthy name of “non-contact ink jet thermo bubble printing technology.” In essence, the technique, for which the company holds close to 100 patents, prints sensors on a microarray. The manufacturing process can be likened to newspaper printing, as it costs very little to print each individual copy. Each Phalanx microarray sells for about US$100, while those of competitors go for US$1,000 or more, Lee Sheng-wan says.
The Taiwan company’s customer list includes hospitals, most of which are in mainland China and the United States, and well-known clients like the US National Aeronautics and Space Administration (NASA). NASA researchers use the Taiwan-made microarrays to compare the gene expression in mice that have flown in space with that of control subjects that have remained on Earth, according to Lee Sheng-wan.
Drug developers also find Phalanx’s microarrays extremely useful, Lee Sheng-wan says. “Pharmaceutical companies want to know which gene makes you sick and which one prevents you from getting sick,” she notes. “And they want to avoid missing the target. They don’t want to spend many millions of dollars on clinical trials only to find out that their drug hits the wrong gene.”
A growing emphasis on testing to determine the relationship between drug action and human genetic variability is also expected to drive future biochip demand. Such testing is crucial for drugs like blood thinners, which are used to prevent clotting, as the thinners can be very helpful for some patients but have severe detrimental effects for others. DNA testing of would-be blood thinner recipients could be used to determine how well they tolerate the drugs and calculate the appropriate dosage accurately.
Phalanx is the only biotech company in the world that manufactures microarrays as well as provides testing of submitted biological samples, Lee Sheng-wan says. She believes the company will be able to continue its current 60-percent annual growth and develop a bigger international presence by expanding further into the mainland Chinese market and signing more service contracts with global pharmaceutical players.
The European Union’s (EU) recent ban on animal testing for cosmetics could add further impetus to Phalanx’s growth momentum, as biochip testing offers a safe, effective alternative, Lee Sheng-wan says. “In animal tests, you can only check how the animals look, eat and defecate, or you can dissect their livers to see if there’s damage,” she says. “But you obtain many times more information with microarrays.”
Student teams led by Peter Wu, front, of Hsinchu’s National Chiao Tung University are creating biochips targeting blindness, deafness and schizophrenia, among other disorders. (Photo Courtesy of Peter Wu)
Obvious Savings
In another trend likely to spur growth in the biochip market, IEK manager Huang Yen-chen (黃彥臻) observes that US health insurers have begun asking patients to undergo DNA testing to determine the potential effectiveness of specific treatments. Avoiding ineffective treatments not only yields faster improvement in patient health, but also leads to obvious savings in time and resources. “In this way, insurers can save enormous amounts of money,” Huang says.
Huang notes that the long-term outlook for the biochip industry is not entirely sunny, as many regulatory issues await resolution and the emerging sector still suffers from a lack of technology integration and standardization. Nevertheless, he is positive that such challenges will be overcome and that new advances will bring additional opportunities. “The next five to 10 years will bring great strides in nanotechnology and the development of biomarkers,” Huang says, explaining that the latter are traceable substances that are ingested by patients and enable biochips to test organ function.
While a major focus of biochip research and development in Taiwan centers on relatively pedestrian DNA testing and microarrays, other efforts have a decidedly more science-fiction feel. At the Biomedical Electronics Translational Research Center (BETRC) of National Chiao Tung University in Hsinchu, for example, teams are creating biochips designed to be implanted into the human body. The teams are directed by former Chiao Tung president, renowned electronics engineering chair and current head of the National Program on Nano Technology Peter Wu (吳重雨).
Each team focuses on a specific disease or disorder of the human nervous system. The team targeting blindness is working on a biochip that will function as an artificial retina, for example, while others are developing chips to control or treat Alzheimer’s disease, bipolar disorder, deafness, epilepsy, Parkinson’s disease and schizophrenia.
“Sufferers of retinitis pigmentosa, a genetic disease, experience the gradual dying of the photoreceptor of their retina, which leads to blindness,” Wu says of the artificial retina project. A retina chip that helps such patients see even a low-resolution image would yield a huge improvement in their quality of life, as such vision helps individuals recognize obstacles and navigate crosswalks, Wu notes.
“Our method involves implanting a chip that is powered by its own solar cells under the retina,” Wu says. “The chip generates electrical pulses that trigger the optic nerve, depending on the outside image.” In turn, the nerve sends impulses to the brain’s vision center.
One of Wu’s main aims is to reduce the price of such medical devices. An artificial retina currently on the market costs US$100,000, he says, adding that such a price “is not affordable for the general public.”
A research center at National Chiao Tung University is developing an implantable, wireless chip to control epileptic seizures. (Photo Courtesy of Biomedical Electronics Translational Research Center)
BETRC’s artificial retina chip will soon be tested on pigs. After that is completed sometime in 2014, the university team plans to transfer the technology to a medical device manufacturer, which will be responsible for running clinical trials involving human test subjects, Wu says.
Another BETRC team is working on an implantable, wireless chip designed to control epileptic seizures. “About 70 million people worldwide suffer from epilepsy; 5 percent of them cannot be treated with medicine,” Wu says. “The current method for helping them involves surgery, but the procedure carries the high risk that the patient will lose vision, memory or emotional function.” The epilepsy chip is currently being tested on animals and the team aims to begin human trials in 2014.
The device, which is implanted directly on the surface of the brain, is referred to as a system-on-chip (SOC) because it contains a built-in brain wave sensor, amplifier and bio-signal processor. When brain waves indicating the early onset of an epileptic seizure are detected, the chip releases electrical pulses that stimulate the brain and suppress the seizure. From detection to electrical stimulation, the whole process takes just 0.8 seconds.
Amazingly, the device would never have to be retrieved after implantation. The chip emits wireless diagnostic signals that can be read by doctors, and servicing and adjustments can also be made wirelessly. Instead of being recharged via a physical connection that passes through the patient’s skin, voltage is topped up by directing a 13-megahertz radio wave at the device’s wireless charging coil.
BETRC’s funding comes from the central government’s NT$50 billion (US$1.7 billion) Aim for the Top University Project (ATP), which was launched in 2005. ATP’s goals are to help at least one of Taiwan’s 12 leading universities enter the ranks of the world’s top 100 universities and see 10 university departments or research centers gain recognition as “world class” research institutions.
In Wu’s view, the government’s support of local biochip and medical device research is wholly justified because it will result in economic and health benefits. “People see the stagnation in ICT [information and communications technology] revenue growth,” Wu says. “It’s difficult to maintain growth without revolutionary new products. But by leveraging Taiwan’s ICT manufacturing expertise and applying it in the medical field, we’re heralding a new age for Taiwan’s semiconductor industry and human health.”
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Jens Kastner is a freelance journalist based in Taipei.
Copyright © 2013 by Jens Kastner