Breaking paradigms in biochemical sensing

Thanks to mapping of the human genome, new types of sensors for earlier detection of medical conditions are now possible

BY JOSE FERNANDEZ VILLASENOR, M.D.,E.E
Freescale Semiconductor
www.freescale.com

You may remember the race to map the human genome that started during the 1990s. The goal of the project was to determine the sequence of chemical base pairs of the DNA. As a medical student back then, I remember some classroom ethics discussions about what would eventually happen with this race between the U.S. Department of Energy’s Office of Science and a prívate company, Celera Genomics, to determine the human genome. Would there be patent protection of the human genome if such information could become a basis for business?

It was clear back then that mapping the human genome could have significant impact on medicine and pharmacology, and we are clearly seeing the result of that effort today. But before we explore some of the implications of this work, let’s go back a little and examine what the human genome is.

The human genome

The human genome is the information contained in our cell’s DNA. This double chain of two polymers of units, called nucleotides, have backbones made of sugars and phosphate (see Fig. 1 ). A specific sequence of bases can be translated to create proteins outside of the cell nucleus. The ribosomes and these proteins either affect a behavior of the same cell or can be ejected into the blood stream to produce a response in a distant organ/cell.

Fig. 1: DNA double helix.

The sequence of bases that created a protein is called a gene, and the complete genes of our DNA form the human genome. Your DNA is inherited from your parents in the form of chromosomes. One set of the pair of chromosomes comes from the father and the other from the mother.

When there are mutations in the DNA, which are not as uncommon as you might think, it might affect the expression of certain proteins (see Fig. 2 ), which in turn, generates a genetic disorder like Down syndrome, cystic fibrosis, hemochromatosis, hemophilia, and Turner syndrome, among others.

Fig. 2: Gene expression and protein creation.

But other genetic problems might not be as readily evident, like Diabetes Mellitus Type 1, in which your pancreas does not produce any insulin at all, or some other diseases that might appear in not such early stages of life. For instance, Diabetes Mellitus tType 2 occurs when a defective insulin gene (or mutated one) stops doing its function, becomes resistant, and other risk factors (obesity, high blood pressure, and sedentarism) trigger the appearance of the chronic degenerative disease.

We can say that, in some way, all the diseases and conditions you’ve had in the past, have now, or will have in the future are related to your human genome. That said, I think we can picture how important the issue on patenting the human genome could be, and the interest that pharmaceutical, medical, healthcare, and private companies have in being a part of this.

The current challenge

Now that the human genome is out in the open, the problem is that we do not have a complete picture of how the genes, proteins, and environmental factors interact. Mapping the genome was just the first step in this new era of medicine, in which we will be able after understanding the dynamics of our human genome to create a customized solution for each patient based in his or her own genetic information.

Imagine being able to select the appropriate dosage of a drug based on your own genetic information, or being able to predict what kind of diseases you may be more susceptible to. This would go a long ways towards preventative medicine, but there would be major concern regarding insurance policies and patient’s security.

I think that early stage detection of potentially life-risking disease conditions, as well as easily accessible, low-cost detection devices for the general population, should be the first stage of this investigation. Why wait until you need triple or quadruple coronary cardiac bypass surgery if you could easily detect, at an early stage, the genetic risk factors for diabetes, hypercholesterolemia, obesity, or arterial hypertension? Early detection can lead to correction with appropriate medical treatment and changes to the patient’s lifestyle.

The reality is these tests are not commonly performed on patients worldwide. Sometimes it is because the patient do not make regular visits to the doctor’s office, and they wait until they have a symptom they can no longer ignore. Other times it is because these tests are not available to the general population, or doctors only screen when they are suspicious of a condition.

Think about a suspected pregnancy. Most women in the industrialized world do home testing before confirmation of the pregnancy by their obstetrician / gynecologist. They prefer to do a simple urine test (which, by the way, does not actually confirm the pregnancy at all). These tests are low-cost and available to everyone without the need for a prescription. The way these home tests work is simple. The protein, antigen, or antibody to be detected, in this case human chorionic gonadotropin (better known as hCG), reacts to the chemical in the testing strip and changes its color.

The problem is that this is a yes-or-no test: either you have the particle or you don’t. Knowing the amount or quantity of this particle, however, is useful for the diagnosis as well. An abnormally high level of hCG could also mean other potentially serious pathologies, like multiple pregnancy or molar pregnancy (an abnormal form of pregnancy wherein a non-viable fertilized egg implants in the uterus and converts a normal pregnancy into an abnormal one which will fail to come to term). On the other hand, a low levels can indicate a possible miscarriage, a blighted ovum, or an ectopic pregnancy.

Breaking paradigms

A new generation of biochemical sensors being developed by Freescale should be available to the general population for not only giving qualitative results but also quantitative results. The sensors are based on ion-sensitive field-effect transistors (IsFETs, see Fig. 3 ).

Fig. 3: Diagram (a) shows the physical distribution of the MOSFET electrical contacts (B, D, G, and S) and its sensitive MIM plates (SP/RE) within the chip area, while diagram (b) is a top view of the available SP/RE configurations.

In these sensors, by using metal-insulator-metal (MIM) structures integrated in series to the gate of submicron MOSFET devices, highly sensitive and ultra-low-power pH sensors can be obtained. One MIM capacitor enables external polarization of the MOSFET device, while a second MIM capacitor is connected to a sensing plate whose surface is either a thick polyimide layer or the last metallization level. The electrochemical response of these surfaces to pH buffer solutions resembles that of ISFET devices whose pH sensitivity is dependent on the type of surface material being exposed.

The IsFETs are then used to create immunological-sensitive FETs (ImFETs), which can be used to detect not only pH, but also antigens and antibodies of specific pathogens that cause a wide array of infectious diseases that could be markers used to detect chronic degenerative diseases.

New needs in the world can be solved with a new generation of medical sensors. This means breaking the paradigms of optical tests and moving to the electrochemical space with more reliable sensors that can give detailed results of the quantities of the specific particle that you want to measure.

Semiconductor companies should and must turn their eyes to this and enable the OEMs with new low cost, low power specifications. Taking advantage of the new era of genetics-based medicine, with high ethical standards and the patient’s wellbeing should always be our main concern. ■